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Azad MG, Russell T, Gu X, Zhao X, Richardson V, Wijesinghe TP, Babu G, Guo X, Kaya B, Dharmasivam M, Deng Z, Richardson DR. NDRG1 and its Family Members: More than Just Metastasis Suppressor Proteins and Targets of Thiosemicarbazones. J Biol Chem 2025:110230. [PMID: 40378957 DOI: 10.1016/j.jbc.2025.110230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2025] [Revised: 04/19/2025] [Accepted: 05/05/2025] [Indexed: 05/19/2025] Open
Abstract
N-Myc downstream regulated gene-1 (NDRG1) and the other three members of this family (NDRG2, 3, and 4) play various functional roles in the cellular stress response, differentiation, migration, and development. These proteins are involved in regulating key signaling proteins and pathways that are often dysregulated in cancer, such as EGFR, PI3K/AKT, c-Met, and the Wnt pathway. NDRG1 is the primary, well-examined member of the NDRG family, and is generally characterized as a metastasis suppressor that inhibits the first step in metastasis, the epithelial-mesenchymal transition. While NDRG1 is well-studied, emerging evidence suggests NDRG2, NDRG3, and NDRG4 also play significant roles in modulating oncogenic signaling and cellular homeostasis. NDRG family members are regulated by multiple mechanisms, including transcriptional control by hypoxia-inducible factors, p53, and Myc, as well as post-translational modifications such as phosphorylation, ubiquitination, and acetylation. Pharmacological targeting of the NDRG family is a therapeutic strategy against cancer. For instance, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) have been extensively shown to up-regulate NDRG1 expression, leading to metastasis suppression and inhibition of tumor growth in multiple cancer models. Similarly, targeting NDRG2 demonstrates its pro-apoptotic and anti-proliferative effects, particularly in glioblastoma and colorectal cancer. This review provides a comprehensive analysis of the structural features, regulatory mechanisms, and biological functions of the NDRG family and their roles in cancer and neurodegenerative diseases. Additionally, NDRG1-4 are explored as therapeutic targets in oncology, focusing on recent advances in anti-cancer agents that induce the expression of these proteins. Implications for future research and clinical applications are also discussed.
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Affiliation(s)
- Mahan Gholam Azad
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Tiffany Russell
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Xuanling Gu
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Xiao Zhao
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Vera Richardson
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Tharushi P Wijesinghe
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Golap Babu
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Xinnong Guo
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Busra Kaya
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Mahendiran Dharmasivam
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Zhao Deng
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Des R Richardson
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia; Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
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Tang T, Liang H, Han Y, Cong Z, Wang H, Wei P, Zhao G. N-myc downstream-regulated gene 2, co-regulated by transcription factors c-MYC and SP1, reduces cell proliferation by interacting with mTOR in GBM. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167742. [PMID: 39986441 DOI: 10.1016/j.bbadis.2025.167742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 10/20/2024] [Accepted: 02/15/2025] [Indexed: 02/24/2025]
Abstract
NDRG2, a recognized suppressor of tumor cell proliferation, displays downregulation in glioma, yet its specific regulatory mechanisms remain elusive. Our study validated the downregulation of NDRG2 in surgical glioma samples from our center and confirmed its antitumor effects both in vitro and in vivo. Utilizing chromatin immunoprecipitation and dual luciferase reporter assays, we identified MYC and SP1 as negative transcription factors that regulate NDRG2 expression. Furthermore, we identified NDRG2 as a novel binding partner of mTOR, a pivotal regulator of cell growth and proliferation, inhibiting the phosphorylation of mTOR. The downstream signaling pathway of mTOR was then inhibited by overexpression of NDRG2. It suggested a potential mechanism by which NDRG2 exerted its antitumor function. Our findings shed light on the intricate regulatory network involving NDRG2 in glioma development and offer insights into novel therapeutic strategies targeting this pathway.
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Affiliation(s)
- Ting Tang
- Department of Neurosurgery, Xuanwu Hospital Capital Medical University, Beijing, China; Brain Research Innovation and Transformation Laboratory, Xuanwu Hospital Capital Medical University, Beijing, China; Department of Neurosurgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Hui Liang
- Department of Neurosurgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China; Department of Neurosurgery, The First Affiliated Hospital, Guangxi Medical University, Nanning, China
| | - Yanling Han
- Department of Neurosurgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Zixiang Cong
- Department of Neurosurgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Handong Wang
- Department of Neurosurgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China; Department of Neurosurgery, Benq Medical Center, Nanjing Medical University, Nanjing, China.
| | - Penghu Wei
- Department of Neurosurgery, Xuanwu Hospital Capital Medical University, Beijing, China; Brain Research Innovation and Transformation Laboratory, Xuanwu Hospital Capital Medical University, Beijing, China.
| | - Guoguang Zhao
- Department of Neurosurgery, Xuanwu Hospital Capital Medical University, Beijing, China; Brain Research Innovation and Transformation Laboratory, Xuanwu Hospital Capital Medical University, Beijing, China; Beijing Municipal Geriatric Medical Research Center, Beijing 100053, China.
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Liu M, Chen J, Sun M, Zhang L, Yu Y, Mi W, Ma Y, Wang G. Protection of Ndrg2 deficiency on renal ischemia-reperfusion injury via activating PINK1/Parkin-mediated mitophagy. Chin Med J (Engl) 2024; 137:2603-2614. [PMID: 38407220 PMCID: PMC11556958 DOI: 10.1097/cm9.0000000000002957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Indexed: 02/27/2024] Open
Abstract
BACKGROUND Renal ischemia-reperfusion (R-I/R) injury is the most prevalent cause of acute kidney injury, with high mortality and poor prognosis. However, the underlying pathological mechanisms are not yet fully understood. Therefore, this study aimed to investigate the role of N-myc downstream-regulated gene 2 ( Ndrg2 ) in R-I/R injury. METHODS We examined the expression of Ndrg2 in the kidney under normal physiological conditions and after R-I/R injury by immunofluorescence staining, real-time polymerase chain reaction, and western blotting. We then detected R-I/R injury in Ndrg2-deficient ( Ndrg2-/- ) mice and wild type ( Ndrg2+/+ ) littermates in vivo , and detected oxygen and glucose deprivation and reperfusion (OGD-R) injury in HK-2 cells. We further conducted transcriptomic sequencing to investigate the role of Ndrg2 in R-I/R injury and detected levels of oxidative stress and mitochondrial damage by dihydroethidium staining, biochemical assays, and western blot. Finally, we measured the levels of mitophagy in Ndrg2+/+ and Ndrg2-/- mice after R-I/R injury or HK-2 cells in OGD-R injury. RESULTS Ndrg2 was primarily expressed in renal proximal tubules and its expression was significantly decreased 24 h after R-I/R injury. Ndrg2-/- mice exhibited significantly attenuated R-I/R injury compared to Ndrg2+/+ mice. Transcriptomics profiling showed that Ndrg2 deficiency induced perturbations of multiple signaling pathways, downregulated inflammatory responses and oxidative stress, and increased autophagy following R-I/R injury. Further studies revealed that Ndrg2 deficiency reduced oxidative stress and mitochondrial damage. Notably, Ndrg2 deficiency significantly activated phosphatase and tensin homologue on chromosome ten-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy. The downregulation of NDRG2 expression significantly increased cell viability after OGD-R injury, increased the expression of heme oxygenase-1, decreased the expression of nicotinamide adenine dinucleotide phosphate oxidase 4, and increased the expression of the PINK1/Parkin pathway. CONCLUSION Ndrg2 deficiency might become a therapy target for R-I/R injury by decreasing oxidative stress, maintaining mitochondrial homeostasis, and activating PINK1/Parkin-mediated mitophagy.
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Affiliation(s)
- Min Liu
- Department of Anesthesiology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
| | - Jianwen Chen
- Department of Nephrology, The First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People’s Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing 100853, China
| | - Miao Sun
- Department of Anesthesiology, The First Affiliated Hospital, Jinzhou Medical University, Jinzhou, Liaoning 121000, China
| | - Lixia Zhang
- Department of Burn and Plastic Surgery, The Fourth Medical Center of Chinese PLA General Hospital, Beijing 100048, China
| | - Yao Yu
- Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, China
| | - Weidong Mi
- Department of Anesthesiology, Chinese PLA General Hospital, Beijing 100853, China
| | - Yulong Ma
- Department of Anesthesiology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Guyan Wang
- Department of Anesthesiology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
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Ahn CH, Kim JH, Shim HW, Shin WJ, Cho YA, Yoon HJ. Biological and prognostic significance of NDRG2 downregulation in oral squamous cell carcinoma. Oral Dis 2024; 30:4287-4302. [PMID: 38887830 DOI: 10.1111/odi.15045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 05/14/2024] [Accepted: 06/04/2024] [Indexed: 06/20/2024]
Abstract
OBJECTIVE Downregulation of N-myc downstream-regulated gene 2 (NDRG2), a tumor suppressor gene, has been associated with poor clinical outcomes in various cancers. However, the prognostic significance of NDRG2 in oral squamous cell carcinoma (OSCC) remains unknown. This study aimed to evaluate the prognostic value of NDRG2 downregulation in OSCC and to elucidate the mechanism by which NDRG2 is downregulated and the biological role of NDRG2 in tumor progression. METHODS Immunohistochemical and in silico analyses of NDRG2 expression were performed, and the correlation between NDRG2 expression and clinicopathological data was analyzed. The effect of NDRG2 knockdown on the biological behavior of OSCC cells was investigated and the effect of 5-aza-2'-deoxycytidine (5-aza-dC) on NDRG2 expression was determined. RESULTS NDRG2 expression was significantly downregulated and DNA hypermethylation of NDRG2 was frequently found in head and neck SCC, including OSCC. Low NDRG2 expression was significantly correlated with adverse clinicopathological features and worse survival in OSCC. NDRG2 knockdown could enhance the oncogenic properties of OSCC cells. NDRG2 mRNA levels in OSCC cells could be restored by 5-aza-dC. CONCLUSION Downregulation of NDRG2 promotes tumor progression and predicts poor prognosis in OSCC. Therefore, restoration of NDRG2 expression may be a potential therapeutic strategy in OSCC.
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Affiliation(s)
- Chi-Hyun Ahn
- Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, South Korea
| | - Ji-Hoon Kim
- Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, South Korea
| | - Hye-Won Shim
- Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, South Korea
- Department of Dentistry, Inje University Ilsan Paik Hospital, Goyang, South Korea
| | - Wui-Jung Shin
- Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, South Korea
| | - Young-Ah Cho
- Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, South Korea
| | - Hye-Jung Yoon
- Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, South Korea
- Department of Oral Pathology, Seoul National University Dental Hospital, Seoul, South Korea
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Liu XH, Zhang LY, Liu XY, Zhang JG, Hu YY, Zhao CG, Xian XH, Li WB, Zhang M. Transformation of A1/A2 Astrocytes Participates in Brain Ischemic Tolerance Induced by Cerebral Ischemic Preconditioning via Inhibiting NDRG2. Neurochem Res 2024; 49:1665-1676. [PMID: 38411782 DOI: 10.1007/s11064-024-04134-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Revised: 01/04/2024] [Accepted: 02/20/2024] [Indexed: 02/28/2024]
Abstract
Cerebral ischemic preconditioning (CIP) has been shown to improve brain ischemic tolerance against subsequent lethal ischemia. Reactive astrocytes play important roles in cerebral ischemia-reperfusion. Recent studies have shown that reactive astrocytes can be polarized into neurotoxic A1 phenotype (C3d) and neuroprotective A2 phenotype (S100A10). However, their role in CIP remains unclear. Here, we focused on the role of N-myc downstream-regulated gene 2 (NDRG2) in regulating the transformation of A1/A2 astrocytes and promoting to brain ischemic tolerance induced by CIP. A Sprague Dawley rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) was used. Rats were divided into the following six groups: (1) sham group; (2) CIP group: left middle cerebral artery was blocked for 10 min; (3) MCAO/R group: left middle cerebral artery was blocked for 90 min; (4) CIP + MCAO/R group: CIP was performed 72 h before MCAO/R; (5) AAV-NDRG2 + CIP + MCAO/R group: adeno-associated virus (AAV) carrying NDRG2 was administered 14 days before CIP + MCAO/R; (6) AAV-Ctrl + CIP + MCAO/R group: empty control group. The rats were subjected to neurological evaluation 24 h after the above treatments, and then were sacrificed for 2, 3, 5-triphenyltetraolium chloride staining, thionin staining, immunofluorescence and western blot analysis. In CIP + MCAO/R group, the neurological deficit scores decreased, infarct volume reduced, and neuronal density increased compared with MCAO/R group. Notably, CIP significantly increased S100A10 expression and the number of S100A10+/GFAP+ cells, and also increased NDRG2 expression. MCAO/R significantly decreased S100A10 expression and the number of S100A10+/GFAP+ cells yet increased C3d expression and the number of C3d+/GFAP+ cells and NDRG2 expression, and these trends were reversed by CIP + MCAO/R. Furthermore, over-expression of NDRG2 before CIP + MCAO/R, the C3d expression and the number of C3d+/GFAP+ cells increased, while S100A10 expression and the number of S100A10+/GFAP+ cells decreased. Meanwhile, over-expression of NDRG2 blocked the CIP-induced brain ischemic tolerance. Taken together, these results suggest that CIP exerts neuroprotective effects against ischemic injury by suppressing A1 astrocyte polarization and promoting A2 astrocyte polarization via inhibiting NDRG2 expression.
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Affiliation(s)
- Xiao-Hua Liu
- Department of Pathophysiology, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang, Hebei, 050017, People's Republic of China
- Department of Physiology, Shijiazhuang Medical College, Shijiazhuang, 050000, People's Republic of China
| | - Ling-Yan Zhang
- Department of Pathophysiology, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang, Hebei, 050017, People's Republic of China
- Hebei Key Laboratory of Critical Disease Mechanism and intervention, Shijiazhuang, 050017, People's Republic of China
| | - Xi-Yun Liu
- Department of Pathophysiology, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang, Hebei, 050017, People's Republic of China
| | - Jing-Ge Zhang
- Department of Pathophysiology, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang, Hebei, 050017, People's Republic of China.
- Hebei Key Laboratory of Critical Disease Mechanism and intervention, Shijiazhuang, 050017, People's Republic of China.
| | - Yu-Yan Hu
- Department of Pathophysiology, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang, Hebei, 050017, People's Republic of China
- Hebei Key Laboratory of Critical Disease Mechanism and intervention, Shijiazhuang, 050017, People's Republic of China
| | - Chen-Guang Zhao
- Department of foreign language, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050017, People's Republic of China
| | - Xiao-Hui Xian
- Department of Pathophysiology, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang, Hebei, 050017, People's Republic of China
- Hebei Key Laboratory of Critical Disease Mechanism and intervention, Shijiazhuang, 050017, People's Republic of China
| | - Wen-Bin Li
- Department of Pathophysiology, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang, Hebei, 050017, People's Republic of China
- Hebei Key Laboratory of Critical Disease Mechanism and intervention, Shijiazhuang, 050017, People's Republic of China
| | - Min Zhang
- Department of Pathophysiology, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang, Hebei, 050017, People's Republic of China.
- Hebei Key Laboratory of Critical Disease Mechanism and intervention, Shijiazhuang, 050017, People's Republic of China.
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Chen T, Xiong Y, Deng C, Hu C, Li M, Quan R, Yu X. NDRG2 alleviates photoreceptor apoptosis by regulating the STAT3/TIMP3/MMP pathway in mice with retinal degenerative disease. FEBS J 2024; 291:986-1007. [PMID: 38037211 DOI: 10.1111/febs.17021] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 10/05/2023] [Accepted: 10/29/2023] [Indexed: 12/02/2023]
Abstract
Photoreceptor apoptosis is the main pathological feature of retinal degenerative diseases; however, the underlying molecular mechanism has not been elucidated. Recent studies have shown that N-myc downstream regulated gene 2 (NDRG2) exerts a neuroprotective effect on the brain and spinal cord. In addition, our previous studies have confirmed that NDRG2 is expressed in mouse retinal photoreceptors and counteracts N-methyl-N-nitrosourea (MNU)-induced apoptosis. However, the underlying molecular mechanism remains unclear. In this study, we observed that the expression of NDRG2 was not only significantly inhibited in photoreceptors after MNU treatment but also after hydrogen peroxide treatment, and photoreceptor apoptosis was alleviated or aggravated after overexpression or knockdown of NDRG2 in the 661W photoreceptor cell line, respectively. The apoptosis inhibitor Z-VAD-FMK rescued photoreceptor apoptosis induced by MNU after NDRG2 knockdown. Next, we screened and identified tissue inhibitor of metalloproteinases 3 (TIMP3) as the downstream molecule of NDRG2 in 661W cells by using quantitative real-time polymerase chain reaction. TIMP3 exerts a neuroprotective effect by inhibiting the expression of matrix metalloproteinases (MMPs). Subsequently, we found that signal transducer and activator of transcription 3 (STAT3) mediated the NDRG2-associated regulation of TIMP3. Finally, we overexpressed NDRG2 in mouse retinal tissues by intravitreally injecting an adeno-associated virus with mouse NDRG2 in vivo. Results showed that NDRG2 upregulated the expression of phospho-STAT3 (p-STAT3) and TIMP3, while suppressing MNU-induced photoreceptor apoptosis and MMP expression. Our findings revealed how NDRG2 regulates the STAT3/TIMP3/MMP pathway and uncovered the molecular mechanism underlying its neuroprotective effect on mouse retinal photoreceptors.
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Affiliation(s)
- Tao Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Institute of Molecular and Translational Medicine, Xi'an Jiaotong University, China
| | - Yecheng Xiong
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Institute of Molecular and Translational Medicine, Xi'an Jiaotong University, China
| | - Chunlei Deng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Institute of Molecular and Translational Medicine, Xi'an Jiaotong University, China
| | - Chengbiao Hu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Institute of Molecular and Translational Medicine, Xi'an Jiaotong University, China
| | - Mengxing Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Institute of Molecular and Translational Medicine, Xi'an Jiaotong University, China
| | - Rui Quan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Institute of Molecular and Translational Medicine, Xi'an Jiaotong University, China
| | - Xiaorui Yu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Institute of Molecular and Translational Medicine, Xi'an Jiaotong University, China
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, China
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Zhong X, He Z, Yin L, Fan Y, Tong Y, Kang Y, Bi Q. Glutamine metabolism in tumor metastasis: Genes, mechanisms and the therapeutic targets. Heliyon 2023; 9:e20656. [PMID: 37829798 PMCID: PMC10565784 DOI: 10.1016/j.heliyon.2023.e20656] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 09/25/2023] [Accepted: 10/03/2023] [Indexed: 10/14/2023] Open
Abstract
Cancer cells frequently change their metabolism from aerobic glycolysis to lipid metabolism and amino acid metabolism to adapt to the malignant biological behaviours of infinite proliferation and distant metastasis. The significance of metabolic substances and patterns in tumour cell metastasis is becoming increasingly prominent. Tumour metastasis involves a series of significant steps such as the shedding of cancer cells from a primary tumour, resistance to apoptosis, and colonisation of metastatic sites. However, the role of glutamine in these processes remains unclear. This review summarises the key enzymes and transporters involved in glutamine metabolism that are related to the pathogenesis of malignant tumour metastasis. We also list the roles of glutamine in resisting oxidative stress and promoting immune escape. Finally, the significance of targeting glutamine metabolism in inhibiting tumour metastasis was proposed, research in this field improving our understanding of amino acid metabolism rewiring and simultaneously bringing about new and exciting therapeutic prospects.
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Affiliation(s)
- Xugang Zhong
- Department of Orthopedics, Zhejiang Provincial People's Hospital, Hangzhou, China
| | - Zeju He
- Department of Orthopedics, Zhejiang Provincial People's Hospital, Hangzhou, China
- Department of Orthopedics, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Li Yin
- Department of Orthopedics, Zhejiang Provincial People's Hospital, Hangzhou, China
- Department of Orthopedics, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yong Fan
- Department of Orthopedics, Zhejiang Provincial People's Hospital, Hangzhou, China
- Department of Orthopedics, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yu Tong
- Department of Orthopedics, Zhejiang Provincial People's Hospital, Hangzhou, China
- Department of Orthopedics, Hangzhou Medical College People's Hospital, Hangzhou, China
| | - Yao Kang
- Department of Orthopedics, Zhejiang Provincial People's Hospital, Hangzhou, China
- Department of Orthopedics, Hangzhou Medical College People's Hospital, Hangzhou, China
| | - Qing Bi
- Department of Orthopedics, Zhejiang Provincial People's Hospital, Hangzhou, China
- Department of Orthopedics, Hangzhou Medical College People's Hospital, Hangzhou, China
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Kurdi M, Fadul MM, Alkhayyat S, Sabbagh AJ, Alsinani T, Alkhotani A, Mulla N, Mehboob R, Fathaddin AA, Bamaga A, Faizo E, Baeesa S. The synergistic effect of IDH mutation and NDRG-2 dysregulation in the progression of WHO-grade 4 astrocytomas. Pathol Res Pract 2023; 248:154733. [PMID: 37536020 DOI: 10.1016/j.prp.2023.154733] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 07/18/2023] [Accepted: 07/31/2023] [Indexed: 08/05/2023]
Abstract
BACKGROUND NDRG2 is a tumour suppressor gene involved in tumor growth inhibition. Its effect on tumour recurrence remains controversial. The aim of this study is to explore the dual effect of IDH mutation and NDRG2 dysregulation in WHO-Grade 4 astrocytoma recurrence. METHODS A group of 36 patients with WHO-Grade 4 astrocytoma were examined for NDRG2 expression using protein and gene expression assays. The relationship between IDH, NDRG2 protein and gene expressions, and recurrence-free interval [RFI] was explored. RESULTS The mean patients age in this study was 45-years with 21 males and 15 females. IDH was mutant in 22 tumors. NDRG2 protein expression was low in 23 tumors, and high in 13 tumors. NDRG2 gene expression was upregulated in 4 tumors and 32 tumors showed NDRG2 gene downregulation. The consistency between two tasting methods of NDRG2 expression was 52.8%. There was a significant statistical difference in RFI among tumors with varying NDRG2 gene expression and IDH mutation [p-value= 0.021]. IDH-mutant tumours with downregulated NDRG2 expression showed late recurrence compared to IDH-wildtype glioblastoma. CONCLUSIONS IDH-mutant WHO Grade-4 astrocytoma with downregulated NDRG2 gene are associated with late tumor recurrence. IDH mutations cause excessive accumulation of D-2-hydroxyglutarate, that may inhibit the activity of TET proteins, potentially leading to DNA hypermethylation and gene silencing.
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Affiliation(s)
- Maher Kurdi
- Department of Pathology, Faculty of Medicine, King Abdulaziz University, Rabigh, Saudi Arabia; Neuromuscular Unit, King Fahad Medical Research Center, Jeddah, Saudi Arabia.
| | - Motaz M Fadul
- Department of Pathology, Faculty of Medicine, King Abdulaziz University, Rabigh, Saudi Arabia
| | - Shadi Alkhayyat
- Department of Internal Medicine, Faculty of Medicine, King Abdulaziz University and Hospital, Jeddah, Saudi Arabia
| | - Abdulrahman J Sabbagh
- Department of Surgery, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Taghreed Alsinani
- Department of Neurosurgery, King Fahad General Hospital, Jeddah, Saudi Arabia
| | - Alaa Alkhotani
- Department of Pathology, College of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Nasser Mulla
- Department of Internal Medicine, Faculty of Medicine, Taibah University, Medina, Saudi Arabia
| | | | - Amany A Fathaddin
- Deprtment of Pathology, College of Medicine, King Saud University and King Saud University Medical City, Riyadh, Saudi Arabia
| | - Ahmed Bamaga
- Deprtment of Pathology, College of Medicine, King Saud University and King Saud University Medical City, Riyadh, Saudi Arabia; Department of Paediatrics, King Abdulaziz University and Hospital, Jeddah, Saudi Arabia
| | - Eyad Faizo
- Department of Surgery, Division of Neurosurgery, University of Tabuk, Tabuk, Saudi Arabia
| | - Saleh Baeesa
- Department of Neurosciences, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia
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Zhang Q, Shi R, Hao M, Feng D, Wu R, Shi M. NDRG2 regulates the formation of reactive astrocyte-derived progenitor cells via Notch signaling pathway after brain traumatic injury in rats. Front Mol Neurosci 2023; 16:1149683. [PMID: 37082656 PMCID: PMC10112515 DOI: 10.3389/fnmol.2023.1149683] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Accepted: 03/21/2023] [Indexed: 04/07/2023] Open
Abstract
In response to traumatic brain injury, a subpopulation of cortical astrocytes is activated, resulting in acquisition of stem cell properties, known as reactive astrocytes-derived progenitor cells (Rad-PCs). However, the underlying mechanisms remain largely unknown during this process. In this study, we examined the role of N-myc downstream-regulated gene 2 (NDRG2), a differentiation- and stress-associated molecule, in Rad-PCs after cortical stab injury in adult rats. Immunohistochemical analysis showed that in the cerebral cortex of normal adult rats, NDRG2 was exclusively expressed in astrocytes. After liu cortical injury, the expression of NDRG2 was significantly elevated around the wound and most cells expressing NDRG2 also expressed GFAP, a reactive astrocyte marker. Importantly, NDRG2-expressing cells were co-labeled with Nestin, a marker for neural stem cells, some of which also expressed cell proliferation marker Ki67. Overexpression of NDRG2 further increased the number of NDRG2/Nestin double-labeling cells around the lesion. In contrast, shRNA knockdown of NDRG2 decreased the number of NDRG2+/Nestin+ cells. Intracerebroventricular administration of stab-injured rats with a Notch antagonist, DAPT, led to a significant decrease in Nestin+/NDRG2+ cells around the injured boundary, but did not affect NDRG2+ cells. Moreover, overexpression or knockdown of NDRG2 led to up- and down-regulation of the expression of Notch intracellular domain NICD and Notch target gene Hes1, respectively. Taken together, these results suggest that NDRG2 may play a role in controlling the formation of Rad-PCs in the cerebral cortex of adult rats following traumatic injury, and that Notch signaling pathway plays a key role in this process.
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Affiliation(s)
- Qinjun Zhang
- Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
- Department of Neurology, Meishan Cardio-Cerebrovascular Disease Hospital, Meishan, Sichuan, China
| | - Rui Shi
- Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Minghua Hao
- Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
- Department of Neurology, Shandong Armed Police General Hospital, Jinan, Shandong, China
| | - Dongyun Feng
- Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Rui Wu
- Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Ming Shi
- Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
- *Correspondence: Ming Shi,
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10
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Ohaegbulam KC, Koethe Y, Fung A, Mayo SC, Grossberg AJ, Chen EY, Sharzehi K, Kardosh A, Farsad K, Rocha FG, Thomas CR, Nabavizadeh N. The multidisciplinary management of cholangiocarcinoma. Cancer 2023; 129:184-214. [PMID: 36382577 DOI: 10.1002/cncr.34541] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 10/11/2022] [Accepted: 10/14/2022] [Indexed: 11/17/2022]
Abstract
Cholangiocarcinoma is a lethal malignancy of the biliary epithelium that can arise anywhere along the biliary tract. Surgical resection confers the greatest likelihood of long-term survivability. However, its insidious onset, difficult diagnostics, and resultant advanced presentation render the majority of patients unresectable, highlighting the importance of early detection with novel biomarkers. Developing liver-directed therapies and emerging targeted therapeutics may offer improved survivability for patients with unresectable or advanced disease. In this article, the authors review the current multidisciplinary standards of care in resectable and unresectable cholangiocarcinoma, with an emphasis on novel biomarkers for early detection and nonsurgical locoregional therapy options.
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Affiliation(s)
- Kim C Ohaegbulam
- Department of Radiation Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - Yilun Koethe
- Department of Interventional Radiology, Oregon Health & Science University, Portland, Oregon, USA
| | - Alice Fung
- Department of Diagnostic Radiology, Oregon Health & Science University, Portland, Oregon, USA
| | - Skye C Mayo
- Department of Surgical Oncology, Oregon Health & Science University, Portland, Oregon, USA
| | - Aaron J Grossberg
- Department of Radiation Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - Emerson Y Chen
- Division of Hematology/Medical Oncology, Oregon Health & Science University, Portland, Oregon, USA
| | - Kaveh Sharzehi
- Division of Gastroenterology and Hepatology, Oregon Health & Science University, Portland, Oregon, USA
| | - Adel Kardosh
- Division of Hematology/Medical Oncology, Oregon Health & Science University, Portland, Oregon, USA
| | - Khashayar Farsad
- Department of Interventional Radiology, Oregon Health & Science University, Portland, Oregon, USA
| | - Flavio G Rocha
- Department of Surgical Oncology, Oregon Health & Science University, Portland, Oregon, USA
| | - Charles R Thomas
- Department of Radiation Medicine, Oregon Health & Science University, Portland, Oregon, USA.,Department of Radiation Oncology, Dartmouth School of Medicine, Hanover, New Hampshire, USA
| | - Nima Nabavizadeh
- Department of Radiation Medicine, Oregon Health & Science University, Portland, Oregon, USA
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11
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The Function of N-Myc Downstream-Regulated Gene 2 (NDRG2) as a Negative Regulator in Tumor Cell Metastasis. Int J Mol Sci 2022; 23:ijms23169365. [PMID: 36012631 PMCID: PMC9408851 DOI: 10.3390/ijms23169365] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 08/18/2022] [Accepted: 08/18/2022] [Indexed: 11/23/2022] Open
Abstract
N-myc downstream-regulated gene 2 (NDRG2) is a tumor-suppressor gene that suppresses tumorigenesis and metastasis of tumors and increases sensitivity to anti-cancer drugs. In this review, we summarize information on the clinicopathological characteristics of tumor patients according to NDRG2 expression in various tumor tissues and provide information on the metastasis inhibition-related cell signaling modulation by NDRG2. Loss of NDRG2 expression is a prognostic factor that correlates with TNM grade and tumor metastasis and has an inverse relationship with patient survival in various tumor patients. NDRG2 inhibits cell signaling, such as AKT-, NF-κB-, STAT3-, and TGF-β-mediated signaling, to induce tumor metastasis, and induces activation of GSK-3β which has anti-tumor effects. Although NDRG2 operates as an adaptor protein to mediate the interaction between kinases and phosphatases, which is essential in regulating cell signaling related to tumor metastasis, the molecular mechanism of NDRG2 as an adapter protein does not seem to be fully elucidated. This review aims to assist the research design regarding NDRG2 function as an adaptor protein and suggests NDRG2 as a molecular target to inhibit tumor metastasis and improve the prognosis in tumor patients.
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12
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Yin X, Yu H, He XK, Yan SX. Prognostic and biological role of the N-Myc downstream-regulated gene family in hepatocellular carcinoma. World J Clin Cases 2022; 10:2072-2086. [PMID: 35321174 PMCID: PMC8895174 DOI: 10.12998/wjcc.v10.i7.2072] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 09/24/2021] [Accepted: 02/10/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The N-Myc downstream-regulated gene (NDRG) family is comprised of four members (NDRG1-4) involved in various important biological processes. However, there is no systematic evaluation of the prognostic of the NDRG family in hepatocellular carcinoma (HCC).
AIM To analyze comprehensively the biological role of the NDRG family in HCC.
METHODS The NDRG family expression was explored using The Cancer Genome Atlas. DNA methylation interactive visualization database was used for methylation analysis of the NDRG family. The NDRG family genomic alteration was assessed using the cBioPortal. Single-sample Gene Set Enrichment Analysis was used to determine the degree of immune cell infiltration in tumors.
RESULTS NDRG1 and NDRG3 were up-regulated in HCC, while NDRG2 was down-regulated. Consistent with expression patterns, high expression of NDRG1 and NDRG3 was associated with poor survival outcomes (P < 0.05). High expression of NDRG2 was associated with favorable survival (P < 0.005). An NDRG-based signature that statistically stratified the prognosis of the patients was constructed. The percentage of genetic alterations in the NDRG family varied from 0.3% to 11.0%, and the NDRG1 mutation rate was the highest. NDRG 1-3 expression was associated with various types of infiltrated immune cells. Gene ontology analysis revealed that organic acid catabolism was the most important biological process related to the NDRG family. Gene Set Enrichment Analysis showed that metabolic, proliferation, and immune-related gene sets were enriched during NDRG1 and NDRG3 high expression and NDRG2 low expression.
CONCLUSION Overexpression of NDRG1 and NDRG3 and down-expression of NDRG2 are correlated with poor overall HCC prognosis. Our results may provide new insights into the indispensable role of NDRG1, 2, and 3 in the development of HCC and guide a promising new strategy for treating HCC.
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Affiliation(s)
- Xin Yin
- Department of Radiation Oncology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Hao Yu
- Department of Radiation Oncology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Xing-Kang He
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Sen-Xiang Yan
- Department of Radiation Oncology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
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13
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MiR-483 Promotes Colorectal Cancer Cell Biological Progression by Directly Targeting NDRG2 through Regulation of the PI3K/AKT Signaling Pathway and Epithelial-to-Mesenchymal Transition. JOURNAL OF HEALTHCARE ENGINEERING 2022; 2022:4574027. [PMID: 35126924 PMCID: PMC8813246 DOI: 10.1155/2022/4574027] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 01/10/2022] [Indexed: 01/10/2023]
Abstract
BACKGROUND Colorectal cancer is the third frequent tumor in the whole world. MiR-483, located at the 11p15.5 locus, acts as an oncogene in multiple tumors. The purpose of this study is to explore the important roles of miR-483 in colorectal cancer. MATERIALS AND METHODS RT-qPCR and western blot were applied to calculate the mRNA levels of miR-483 and genes. The Kaplan-Meier method was conducted to calculate the survival of patients with colorectal cancer. The proliferation and invasive abilities were measured by Methyl Thiazolyl Tetrazolium (MTT) and transwell assays. RESULTS MiR-483 was upregulated in colorectal cancer tissues, and the upregulation of miR-483 predicted poor prognosis of colorectal cancer patients. NDRG2 was a target gene of miR-483 in colorectal cancer. Furthermore, miR-483 has been reported to promote colorectal cancer cell proliferation and invasion through targeting NDRG2 by the PI3K/AKT pathway and epithelial-to-mesenchymal transition (EMT). In addition, the overexpression of miR-483 promoted xenograft growth of LOVO cells. CONCLUSION MiR-483 promoted cell proliferation through the NDRG2/PI3K/AKT pathway and invasion-mediated EMT in colorectal cancer. In view of the multiple mechanisms of molecular immunotherapy, it is necessary to further study the relationship between miR-483 and colorectal cancer, so as to find a more direct and effective treatment method to prevent colorectal cancer.
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14
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Tang T, Wang H, Han Y, Huang H, Niu W, Fei M, Zhu Y. The Role of N-myc Downstream-Regulated Gene Family in Glioma Based on Bioinformatics Analysis. DNA Cell Biol 2021; 40:949-968. [PMID: 34115542 DOI: 10.1089/dna.2020.6216] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Glioma is the most common type of primary tumor in the central nervous system, and the molecular mechanisms remain elusive. N-myc downstream-regulated gene (NDRG) family is reported to take part in the pathogenesis of various diseases, including some preliminary exploration in glioma. However, there has been no bioinformatics analysis of NDRG family in glioma yet. Herein, we focused on the expression changes of NDRGs with their value in predicting patients' prognoses, upstream regulatory mechanisms (DNA mutation, DNA methylation, transcription factors, and microRNA regulation) and gene enrichment analysis based on co-expressed genes with data from public databases. Furthermore, the expression pattern of NDRGs was verified by the paired glioma and peritumoral samples in our institute. It was suggested that NDRGs were differentially expressed genes in glioma. In particular, the lower expression of NDRG2 or NDRG4 could serve as a predictor of higher grade tumor and poorer prognosis. Also, NDRGs might play a crucial role in signal transduction, energy metabolism, and cross-talk among cells in glioma, under the control of a complex regulatory network. This study enables us to better understand the role of NDRGs in glioma and with further research, it may contribute to the development of glioma treatment.
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Affiliation(s)
- Ting Tang
- Department of Neurosurgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, P.R. China
| | - Handong Wang
- Department of Neurosurgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, P.R. China
| | - Yanling Han
- Department of Neurosurgery, Jinling Hospital, Nanjing, P.R. China
| | - Hanyu Huang
- Department of Neurosurgery, Affiliated Jinling Hospital, Nanjing Medical University, Nanjing, P.R. China
| | - Wenhao Niu
- Department of Neurosurgery, Jinling Hospital, Nanjing, P.R. China
| | - Maoxing Fei
- Department of Neurosurgery, Jinling Hospital, Nanjing, P.R. China
| | - Yihao Zhu
- Department of Neurosurgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, P.R. China
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15
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Chen M, Pang DD, Dai SM. Expression Profile of Osteoclasts Following the Stimulation With Interleukin-23 in Mice. Arch Rheumatol 2021; 35:533-544. [PMID: 33758810 PMCID: PMC7945700 DOI: 10.46497/archrheumatol.2020.7510] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Accepted: 05/13/2020] [Indexed: 11/08/2022] Open
Abstract
Objectives
This study aims to analyze the expression profile of osteoclasts (OCs) following the stimulation with interleukin 23 (IL-23) in mice, which would imply the underlying effects of IL-23 on the function of OCs in inflammatory arthritis. Materials and methods
Mature OCs were induced from bone marrow mononuclear cells of 5 male mice (age 6 weeks; weighing 18-20 g) in the presence of macrophage-colony stimulating factor (50 ng/mL) and receptor activator of nuclear factor kappa B ligand (30 ng/mL) in vitro. The Agilent SurePrint G3 Mouse GE V2.0 Microarray was used to analyze the gene expression profile of OCs stimulated with IL-23 (30 ng/mL) or vehicle. The four major IL-23-modulated genes were validated by quantitative real-time polymerase chain reaction (qPCR) analysis. Results
The expression levels of 23 genes were up-regulated and 32 genes were down-regulated by IL-23 stimulation (fold change ≥1.5 and p value <0.05). Among them, there were 37 genes with assigned gene symbols. Gene ontology analysis showed that the IL-23-regulated messenger ribonucleic acids (mRNAs) were related to positive regulation of leukocyte chemotaxis, chemokine-mediated signaling pathway and C-X-C chemokine receptors binding. The pathway analysis showed that the IL-23-regulated mRNAs were related to chemokine signaling pathway and cytokine-cytokine receptor interaction. The significant up-regulation of chemokine (C-X-C motif) ligand 1 and chemokine (C-X-C motif) ligand 2 induced by IL-23 was confirmed by qPCR. In addition, there were 18 long non-coding RNAs that were regulated by IL-23, while their function needs to be confirmed in the future. Conclusion Expression levels of genes related to chemotaxis in OCs were up-regulated by IL-23 in mice, which imply that IL-23 may facilitate chemotaxis of OCs in inflammatory arthritis.
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Affiliation(s)
- Miao Chen
- Department of Rheumatology & Immunology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Dan-Dan Pang
- Department of Rheumatology & Immunology, Changhai Hospital, Second Military Medical University, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Sheng-Ming Dai
- Department of Rheumatology & Immunology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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16
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Rodrigues PM, Olaizola P, Paiva NA, Olaizola I, Agirre-Lizaso A, Landa A, Bujanda L, Perugorria MJ, Banales JM. Pathogenesis of Cholangiocarcinoma. ANNUAL REVIEW OF PATHOLOGY 2021; 16:433-463. [PMID: 33264573 DOI: 10.1146/annurev-pathol-030220-020455] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Cholangiocarcinoma (CCA) encompasses a group of malignancies that can arise at any point in the biliary tree. Although considered a rare cancer, the incidence of CCA is increasing globally. The silent and asymptomatic nature of these tumors, particularly in their early stages, in combination with their high aggressiveness, intra- and intertumor heterogeneity, and chemoresistance, significantly compromises the efficacy of current therapeutic options, contributing to a dismal prognosis. During the last few years, increasing efforts have been made to unveil the etiologies and pathogenesis of these tumors and to develop more effective therapies. In this review, we summarize current findings in the field of CCA, mainly focusing on the mechanisms of pathogenesis, cells of origin, genomic and epigenetic abnormalities, molecular alterations, chemoresistance, and therapies.
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Affiliation(s)
- Pedro M Rodrigues
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
- National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Paula Olaizola
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Nuno A Paiva
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Irene Olaizola
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Alona Agirre-Lizaso
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Ana Landa
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Luis Bujanda
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
- National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Maria J Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
- National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
- National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain
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17
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Lee HY, Son SW, Moeng S, Choi SY, Park JK. The Role of Noncoding RNAs in the Regulation of Anoikis and Anchorage-Independent Growth in Cancer. Int J Mol Sci 2021; 22:ijms22020627. [PMID: 33435156 PMCID: PMC7827914 DOI: 10.3390/ijms22020627] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 01/02/2021] [Accepted: 01/06/2021] [Indexed: 12/11/2022] Open
Abstract
Cancer is a global health concern, and the prognosis of patients with cancer is associated with metastasis. Multistep processes are involved in cancer metastasis. Accumulating evidence has shown that cancer cells acquire the capacity of anoikis resistance and anchorage-independent cell growth, which are critical prerequisite features of metastatic cancer cells. Multiple cellular factors and events, such as apoptosis, survival factors, cell cycle, EMT, stemness, autophagy, and integrins influence the anoikis resistance and anchorage-independent cell growth in cancer. Noncoding RNAs (ncRNAs), such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), are dysregulated in cancer. They regulate cellular signaling pathways and events, eventually contributing to cancer aggressiveness. This review presents the role of miRNAs and lncRNAs in modulating anoikis resistance and anchorage-independent cell growth. We also discuss the feasibility of ncRNA-based therapy and the natural features of ncRNAs that need to be contemplated for more beneficial therapeutic strategies against cancer.
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18
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Uddin MS, Mamun AA, Alghamdi BS, Tewari D, Jeandet P, Sarwar MS, Ashraf GM. Epigenetics of glioblastoma multiforme: From molecular mechanisms to therapeutic approaches. Semin Cancer Biol 2020; 83:100-120. [PMID: 33370605 DOI: 10.1016/j.semcancer.2020.12.015] [Citation(s) in RCA: 107] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 12/21/2020] [Accepted: 12/22/2020] [Indexed: 02/07/2023]
Abstract
Glioblastoma multiforme (GBM) is the most common form of brain cancer and one of the most aggressive cancers found in humans. Most of the signs and symptoms of GBM can be mild and slowly aggravated, although other symptoms might demonstrate it as an acute ailment. However, the precise mechanisms of the development of GBM remain unknown. Due to the improvement of molecular pathology, current researches have reported that glioma progression is strongly connected with different types of epigenetic phenomena, such as histone modifications, DNA methylation, chromatin remodeling, and aberrant microRNA. Furthermore, the genes and the proteins that control these alterations have become novel targets for treating glioma because of the reversibility of epigenetic modifications. In some cases, gene mutations including P16, TP53, and EGFR, have been observed in GBM. In contrast, monosomies, including removals of chromosome 10, particularly q23 and q25-26, are considered the standard markers for determining the development and aggressiveness of GBM. Recently, amid the epigenetic therapies, histone deacetylase inhibitors (HDACIs) and DNA methyltransferase inhibitors have been used for treating tumors, either single or combined. Specifically, HDACIs are served as a good choice and deliver a novel pathway to treat GBM. In this review, we focus on the epigenetics of GBM and the consequence of its mutations. We also highlight various treatment approaches, namely gene editing, epigenetic drugs, and microRNAs to combat GBM.
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Affiliation(s)
- Md Sahab Uddin
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh; Pharmakon Neuroscience Research Network, Dhaka, Bangladesh
| | - Abdullah Al Mamun
- Teaching and Research Division, School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon Tong, Kowloon, Hong Kong Special Administrative Region
| | - Badrah S Alghamdi
- Department of Physiology, Neuroscience Unit, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Devesh Tewari
- Department of Pharmacognosy, School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
| | - Philippe Jeandet
- Research Unit, Induced Resistance and Plant Bioprotection, EA 4707, SFR Condorcet FR CNRS 3417, Faculty of Sciences, University of Reims Champagne-Ardenne, PO Box 1039, 51687, Reims Cedex 2, France
| | - Md Shahid Sarwar
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali-3814, Bangladesh
| | - Ghulam Md Ashraf
- Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
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19
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Xiong YC, Chen T, Yang XB, Deng CL, Ning QL, Quan R, Yu XR. 17β-Oestradiol Attenuates the Photoreceptor Apoptosis in Mice with Retinitis Pigmentosa by Regulating N-myc Downstream Regulated Gene 2 Expression. Neuroscience 2020; 452:280-294. [PMID: 33246060 DOI: 10.1016/j.neuroscience.2020.11.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 07/23/2020] [Accepted: 11/08/2020] [Indexed: 10/22/2022]
Abstract
Retinitis pigmentosa (RP) is a heterogeneous group of retinal degenerative diseases in which the final pathological feature is photoreceptor cell apoptosis. Currently, the pathogenesis of RP remains poorly understood and therapeutics are ineffective. 17β-Oestradiol (βE2) is universally acknowledged as a neuroprotective factor in neurodegenerative diseases and has manifested neuroprotective effects in a light-induced retinal degeneration model. Recently, we identified N-myc downstream regulated gene 2 (NDRG2) suppression as a molecular marker of mouse retinal photoreceptor-specific cell death. βE2 has also been reported to regulate NDRG2 in salivary acinar cells. Therefore, in this study, we investigated whether βE2 plays a protective role in RP and regulates NDRG2 in photoreceptor cells. To this end, we generated RP models and observed that βE2 not only reduced the apoptosis of photoreceptor cells, but also restored the level of NDRG2 expression in RP models. Then, we showed that siNDRG2 inhibits the anti-apoptotic effect of βE2 on photoreceptor cells in a cellular RP model. Subsequently, we used a classic oestrogen receptor (ER) antagonist to attenuate the effects of βE2, suggesting that βE2 exerted its effects on RP models via the classic ERs. In addition, we performed a bioinformatics analysis, and the results indicated that the reported oestrogen response element (ERE) sequence is present in the promoter region of the mouse NDRG2 gene. Overall, our results suggest that βE2 attenuated the apoptosis of photoreceptor cells in RP models by maintaining NDRG2 expression via a classic ER-mediated mechanism.
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Affiliation(s)
- Ye-Cheng Xiong
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Tao Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Xiao-Bei Yang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Chun-Lei Deng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Qi-Lan Ning
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Rui Quan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Xiao-Rui Yu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, Shaanxi 710061, China.
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20
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NDRG2 is expressed on enteric glia and altered in conditions of inflammation and oxygen glucose deprivation/reoxygenation. J Mol Histol 2020; 52:101-111. [PMID: 33205345 DOI: 10.1007/s10735-020-09927-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 11/11/2020] [Indexed: 01/07/2023]
Abstract
Enteric glial cells are more abundant than neurons in the enteric nervous system. Accumulating evidence has demonstrated that enteric glial cells share many properties with astrocytes and play pivotal roles in intestinal diseases. NDRG2 is specifically expressed in astrocytes and is involved in various diseases in the central nervous system. However, no studies have demonstrated the expression of NDRG2 in enteric glial cells. We performed immunostaining of adult mouse tissue, human colon sections, and primary enteric glial cells and the results showed that NDRG2 was widely expressed in enteric glial cells. Meanwhile, our results showed that NDRG2 was upregulated after treatment with pro-inflammatory cytokines and exposure to oxygen glucose deprivation/reoxygenation, indicating that NDRG2 might be involved in these conditions. Moreover, we determined that NDRG2 translocated to the nucleus after treatment with pro-inflammatory cytokines but not after exposure to oxygen glucose deprivation/reoxygenation. This study is the first to show the expression and distribution of NDRG2 in the enteric glia. Our results indicate that NDRG2 might be involved in the pathogenesis of enteric inflammation and ischemia/reperfusion injury. This study shows that NDRG2 might be a molecular target for enteric nervous system diseases.
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21
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Takarada-Iemata M. Roles of N-myc downstream-regulated gene 2 in the central nervous system: molecular basis and relevance to pathophysiology. Anat Sci Int 2020; 96:1-12. [PMID: 33174183 DOI: 10.1007/s12565-020-00587-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 10/30/2020] [Indexed: 12/12/2022]
Abstract
N-myc downstream-regulated gene 2 (NDRG2) is a member of the NDRG family, whose members have multiple functions in cell proliferation, differentiation, and stress responses. NDRG2 is widely distributed in the central nervous system and is uniquely expressed by astrocytes; however, its role in brain function remains elusive. The clinical relevance of NDRG2 and the molecular mechanisms in which it participates have been reported by studies using cultured cells and specimens of patients with neurological disorders. In recent years, genetic tools, including several lines of Ndrg2-knockout mice and virus-mediated gene transfer, have improved understanding of the roles of NDRG2 in vivo. This review aims to provide an update of recent growing in vivo evidence that NDRG2 is involved in brain function, focusing on research of Ndrg2-knockout mice with neurological disorders such as brain tumors, chronic neurodegenerative diseases, and acute brain insults including brain injury and cerebral stroke. These studies demonstrate that NDRG2 plays diverse roles in the regulation of astrocyte reactivity, blood-brain barrier integrity, and glutamate excitotoxicity. Further elucidation of the roles of NDRG2 and their molecular basis may provide novel therapeutic approaches for various neurological disorders.
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Affiliation(s)
- Mika Takarada-Iemata
- Department of Neuroanatomy, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan.
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22
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Ding M, Bu X, Li Z, Xu H, Feng L, Hu J, Wei X, Gao J, Tao Y, Cai B, Liu Y, Qu X, Shen L. NDRG2 ablation reprograms metastatic cancer cells towards glutamine dependence via the induction of ASCT2. Int J Biol Sci 2020; 16:3100-3115. [PMID: 33162818 PMCID: PMC7645990 DOI: 10.7150/ijbs.48066] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 09/21/2020] [Indexed: 01/06/2023] Open
Abstract
Background: Metastasis is the most common cause of lethal outcome in various types of cancers. Although the cell proliferation related metabolism rewiring has been well characterized, less is known about the association of metabolic changes with tumor metastasis. Herein, we demonstrate that metastatic tumor obtained a mesenchymal phenotype, which is obtained by the loss of tumor suppressor NDRG2 triggered metabolic switch to glutamine metabolism. Methods: mRNA-seq and gene expression profile analysis were performed to define the differential gene expressions in primary MEC1 and metastatic MC3 cells and the downstream pathways of NDRG2. NDRG2 regulation of Fbw7-dependent c-Myc stability were determined by immunoprecipitation and protein half-life assay. Luciferase reporter and ChIP assays were used to determine the roles of Akt and c-Myc in mediating NDRG2-dependent regulation of ASCT2 in in both tumor and NDRG2-knockout MEF cells. Finally, the effect of the NDRG2/Akt/c-Myc/ASCT2 signaling on glutaminolysis and tumor metastasis were evaluated by functional experiments and clinical samples. Results: Based on the gene expression profile analysis, we identified metastatic tumor cells acquired the mesenchymal-like characteristics and displayed the increased dependency on glutamine utilization. Further, the gain of NDRG2 function blocked epithelial-mesenchymal transition (EMT) and glutaminolysis, potentially through suppression of glutamine transporter ASCT2 expression. The ASCT2 restoration reversed NDRG2 inhibitory effect on EMT program and tumor metastasis. Mechanistic study indicates that NDRG2 promoted Fbw7-dependent c-Myc degradation by inhibiting Akt activation, and subsequently decreased c-Myc-mediated ASCT2 transcription, in both tumor and NDRG2-knockout MEF cells. Supporting the biological significance, the reciprocal relationship between NDRG2 and ASCT2 were observed in multiple types of tumor tissues, and associated with tumor malignancy. Conclusions: NDRG2-dependent repression of ASCT2 presumably is the predominant route by which NDRG2 rewires glutaminolysis and blocks metastatic tumor survival. Targeting glutaminolytic pathway may provide a new strategy for the treatment of metastatic tumors.
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Affiliation(s)
- Mingchao Ding
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, 710032, China.,State Key Laboratory of Military Stomatology &National Clinical Research Center for Oral Diseases&Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, No. 145 Changle Xi Road, Xi'an, 710032, China
| | - Xin Bu
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, 710032, China
| | - Zhehao Li
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, 710032, China.,Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jiamusi University, Jiamusi, 154002, China
| | - Haokun Xu
- State Key Laboratory of Military Stomatology &National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Department of Oral Anatomy and Physiology and TMD, the Fourth Military Medical University, Xi'an 710032, China
| | - Lin Feng
- Shaanxi University of Chinese Medicine, Xianyang, 712046, China
| | - Junbi Hu
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Xinxin Wei
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, 710032, China.,Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jiamusi University, Jiamusi, 154002, China
| | - Jiwei Gao
- Department of General Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, 710032, China
| | - Yanyan Tao
- Xi'an Peihua University, Xi'an, 710125, China
| | - Bolei Cai
- State Key Laboratory of Military Stomatology &National Clinical Research Center for Oral Diseases&Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, No. 145 Changle Xi Road, Xi'an, 710032, China
| | - Yanpu Liu
- State Key Laboratory of Military Stomatology &National Clinical Research Center for Oral Diseases&Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, No. 145 Changle Xi Road, Xi'an, 710032, China
| | - Xuan Qu
- Shaanxi University of Chinese Medicine, Xianyang, 712046, China
| | - Liangliang Shen
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, 710032, China
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23
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Cheng H, Zhang L, Xia F, Jin L, Liu S, Ren H, Zhu C, Ji Q, Tang J. Astrocytic NDRG2 is critical in the maintenance of neuropathic pain. Brain Behav Immun 2020; 89:300-313. [PMID: 32688030 DOI: 10.1016/j.bbi.2020.07.009] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 07/08/2020] [Accepted: 07/10/2020] [Indexed: 12/22/2022] Open
Abstract
Activation of astrocytes and abnormal synaptic glutamate metabolism are closely associated with the induction and maintenance of neuropathic pain (NP), but the exact mechanism underlying this association remains unclear. N-myc downstream-regulated gene 2 (NDRG2), a novel tumor-suppressor protein and stress-response gene, is involved in the pathogenesis of several neurodegenerative diseases. However, its role in nociceptive transduction has rarely been investigated. Here, we found that NDRG2, which was mainly expressed in the astrocytes in the central nervous system (CNS), was increased in the spinal cord of a spinal nerve ligation (SNL) rat model for NP. Suppression of NDRG2 by intrathecal injection of an NDRG2-RNAi-adenovirus significantly alleviated SNL-induced mechanical and thermal hypersensitivity, as well as elevated astrocytic glutamate transporter 1 (GLT-1) expression and downregulated pro-inflammatory cytokine levels, in the spinal dorsal horn of rats on Day 10 after SNL. Furthermore, in lipopolysaccharide (LPS)-stimulated primary astrocytic cultures derived from neonatal rats, inhibition of NDRG2 significantly reversed both the LPS-induced activation of astrocytes and decreased expression of GLT-1. By contrast, overexpression of NDRG2 by an adenoviral vector carrying NDRG2 resulted in astrocytic activation, aberrant glutamatergic neurotransmission, and spontaneous nociceptive responses in rats. Intrathecal injection of AG490, which is an inhibitor of the Janus tyrosine kinase and signal transducer and activator of the transcription 3 (JAK/STAT3) signaling pathway, significantly attenuated both mechanical and thermal hyperalgesia, as well as inhibited reactive astrocytes and restored normal expression levels of astrocytic GLT-1, in the spinal dorsal horn of NDRG2-overexpression rats. In conclusion, spinal astrocytic NDRG2 is critical in the maintenance of NP. Moreover, NDRG2 modulates astrocytic activation and inflammatory responses via regulating GLT-1 expression through the JAK/STAT3 signaling pathway. Our findings suggested that NDRG2 could be a novel therapeutic target for the treatment of NP.
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Affiliation(s)
- Hao Cheng
- Department of Anesthesiology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Lidong Zhang
- Department of Anesthesiology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Fei Xia
- Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Li Jin
- Department of Anesthesiology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Suting Liu
- Department of Anesthesiology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Hongwei Ren
- Department of Anesthesiology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Chao Zhu
- Department of Spine Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Qing Ji
- Department of Anesthesiology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
| | - Jun Tang
- Department of Anesthesiology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
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24
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Zhu J, Yang LK, Wang QH, Lin W, Feng Y, Xu YP, Chen WL, Xiong K, Wang YH. NDRG2 attenuates ischemia-induced astrocyte necroptosis via the repression of RIPK1. Mol Med Rep 2020; 22:3103-3110. [PMID: 32945444 PMCID: PMC7453600 DOI: 10.3892/mmr.2020.11421] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 11/20/2019] [Indexed: 12/25/2022] Open
Abstract
Cerebral ischemia results in severe brain damage, and is a leading cause of death and long-term disability. Previous studies have investigated methods to activate astrocytes in order to promote repair in injured brain tissue and inhibit cell death. It has previously been shown that N-myc downstream-regulated gene 2 (NDRG2) was highly expressed in astrocytes and associated with cell activity, but the underlying mechanism is largely unknown. The present study generated NDRG2 conditional knockout (Ndrg2-/-) mice to investigate whether NDRG2 can block ischemia-induced astrocyte necroptosis by suppressing receptor interacting protein kinase 1 (RIPK1) expression. This study investigated astrocyte activity in cerebral ischemia, and identified that ischemic brain injuries could trigger RIP-dependent astrocyte necroptosis. The depletion of NDRG2 was found to accelerate permanent middle cerebral artery occlusion-induced necroptosis in the brain tissue of Ndrg2-/- mice, indicating that NDRG2 may act as a neuroprotector during cerebral ischemic injury. The present study suggested that NDRG2 attenuated astrocytic cell death via the suppression of RIPK1. The pharmacological inhibition of astrocyte necroptosis by necrostatin-1 provided neuroprotection against ischemic brain injuries after NDRG2 knockdown. Therefore, NDRG2 could be considered as a potential target for the treatment of cerebral ischemia.
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Affiliation(s)
- Jie Zhu
- Department of Neurosurgery, The 101 Hospital of PLA, School of Medicine, Anhui Medical University, Wuxi, Jiangsu 214044, P.R. China
| | - Li-Kun Yang
- Department of Neurosurgery, The 101 Hospital of PLA, School of Medicine, Anhui Medical University, Wuxi, Jiangsu 214044, P.R. China
| | - Qiu-Hong Wang
- Department of Ophthalmology, Wuxi Second Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214002, P.R. China
| | - Wei Lin
- Department of Neurosurgery, The 101 Hospital of PLA, School of Medicine, Anhui Medical University, Wuxi, Jiangsu 214044, P.R. China
| | - Yi Feng
- Department of Neurosurgery, The 101 Hospital of PLA, School of Medicine, Anhui Medical University, Wuxi, Jiangsu 214044, P.R. China
| | - Ye-Ping Xu
- Department of Neurosurgery, The 101 Hospital of PLA, School of Medicine, Anhui Medical University, Wuxi, Jiangsu 214044, P.R. China
| | - Wei-Liang Chen
- Department of Neurosurgery, The 101 Hospital of PLA, School of Medicine, Anhui Medical University, Wuxi, Jiangsu 214044, P.R. China
| | - Kun Xiong
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, Hunan 410013, P.R. China
| | - Yu-Hai Wang
- Department of Neurosurgery, The 101 Hospital of PLA, School of Medicine, Anhui Medical University, Wuxi, Jiangsu 214044, P.R. China
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25
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Guo H, Yin A, Ma Y, Fan Z, Tao L, Tang W, Ma Y, Hou W, Cai G, Zhuo L, Zhang J, Li Y, Xiong L. Astroglial N-myc downstream-regulated gene 2 protects the brain from cerebral edema induced by stroke. Glia 2020; 69:281-295. [PMID: 32652708 PMCID: PMC7754347 DOI: 10.1002/glia.23888] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Revised: 06/16/2020] [Accepted: 06/26/2020] [Indexed: 01/14/2023]
Abstract
Brain edema is a grave complication of brain ischemia and is the main cause of herniation and death. Although astrocytic swelling is the main contributor to cytotoxic edema, the molecular mechanism involved in this process remains elusive. N‐myc downstream‐regulated gene 2 (NDRG2), a well‐studied tumor suppressor gene, is mainly expressed in astrocytes in mammalian brains. Here, we found that NDRG2 deficiency leads to worsened cerebral edema, imbalanced Na+ transfer, and astrocyte swelling after ischemia. We also found that NDRG2 deletion in astrocytes dramatically changed the expression and distribution of aquaporin‐4 and Na+‐K+‐ATPase β1, which are strongly associated with cell polarity, in the ischemic brain. Brain edema and astrocyte swelling were significantly alleviated by rescuing the expression of astrocytic Na+‐K+‐ATPase β1 in NDRG2‐knockout mouse brains. In addition, the upregulation of astrocytic NDRG2 by lentiviral constructs notably attenuated brain edema, astrocytic swelling, and blood–brain barrier destruction. Our results indicate a particular role of NDRG2 in maintaining astrocytic polarization to facilitate Na+ and water transfer balance and to protect the brain from ischemic edema. These findings provide insight into NDRG2 as a therapeutic target in cerebral edema.
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Affiliation(s)
- Hang Guo
- Department of Anesthesiology, The Seventh Medical Center of Chinese PLA General Hospital, Beijing, China.,Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, The Air Force Military Medical University, Xi'an, China
| | - Anqi Yin
- Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, The Air Force Military Medical University, Xi'an, China.,Department of Anesthesiology, Jinling Hospital, Nanjing, China
| | - Yulong Ma
- Anesthesia and Operation Center, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Ze Fan
- Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, The Air Force Military Medical University, Xi'an, China
| | - Liang Tao
- Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, The Air Force Military Medical University, Xi'an, China
| | - Wenhong Tang
- Department of Anesthesiology, The 960th Hospital of PLA, Jinan, China
| | - Yaqun Ma
- Department of Anesthesiology, The Seventh Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Wugang Hou
- Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, The Air Force Military Medical University, Xi'an, China
| | - Guohong Cai
- Institute of Neuroscience, The Air Force Military Medical University, Xi'an, China
| | - Lixia Zhuo
- Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jian Zhang
- Department of Biochemistry and Molecular Biology, The Air Force Military Medical University, Xi'an, China
| | - Yan Li
- Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, The Air Force Military Medical University, Xi'an, China.,Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Lize Xiong
- Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, The Air Force Military Medical University, Xi'an, China.,Department of Anesthesiology & Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, Tongji University School of Medicine, Shanghai, China
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26
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Li X, Wu X, Luo P, Xiong L. Astrocyte-specific NDRG2 gene: functions in the brain and neurological diseases. Cell Mol Life Sci 2020; 77:2461-2472. [PMID: 31834421 PMCID: PMC11104915 DOI: 10.1007/s00018-019-03406-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2019] [Revised: 11/27/2019] [Accepted: 11/28/2019] [Indexed: 01/07/2023]
Abstract
In recent years, the roles of astrocytes of the central nervous system in brain function and neurological disease have drawn increasing attention. As a member of the N-myc downstream-regulated gene (NDRG) family, NDRG2 is principally expressed in astrocytes of the central nervous system. NDRG2, which is involved in cell proliferation and differentiation, is commonly regarded as a tumor suppressor. In astrocytes, NDRG2 affects the regulation of apoptosis, astrogliosis, blood-brain barrier integrity, and glutamate clearance. Several preclinical studies have revealed that NDRG2 is implicated in the pathogenesis of many neurological diseases not limited to tumors (mostly glioma in the nervous system), such as stroke, neurodegeneration (Alzheimer's disease and Parkinson's disease), and psychiatric disorders (depression and attention deficit hyperactivity disorder). This review summarizes the biological functions of NDRG2 under physiological and pathological conditions, and further discusses the roles of NDRG2 during the occurrence and development of neurological diseases.
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Affiliation(s)
- Xin Li
- Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, 127 Changle Xi Road, Xi'an, 710032, China
| | - Xiuquan Wu
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, 127 Changle Xi Road, Xi'an, 710032, China
| | - Peng Luo
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, 127 Changle Xi Road, Xi'an, 710032, China.
| | - Lize Xiong
- Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, 127 Changle Xi Road, Xi'an, 710032, China.
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27
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NDRG2 gene expression pattern in ovarian cancer and its specific roles in inhibiting cancer cell proliferation and suppressing cancer cell apoptosis. J Ovarian Res 2020; 13:48. [PMID: 32345304 PMCID: PMC7189606 DOI: 10.1186/s13048-020-00649-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Accepted: 04/14/2020] [Indexed: 01/06/2023] Open
Abstract
Background The cancer cell metastasis and the acquisition of chemotherapy resistance remain huge challenge for ovarian cancer treatment. Previously, N-myc downstream-regulated gene 2 (NDRG2) serves as a tumor suppressor for many cancers. Here, we attempted to investigate the specific roles of NDRG2 in ovarian cancer. Methods The expression levels of NDRG2 were detected by qRT-PCR or Immunoblotting. CCK-8 assay was employed to examine the cell viability of ovarian cancer cells. The colony formation ability was determined by colony formation assay. Flow cytometry analyses were performed to detect the cell apoptosis and cell cycle. Xenograft tumor assay was performed to detect the in vivo function of NDRG2. Results We revealed that NDRG2 mRNA expression and protein levels were downregulated within both ovarian cancer tissues and cell lines. The overexpression of NDRG2 dramatically inhibited the cell viability and colony formation and tumor growth, whereas promoted the cell apoptosis, cell cycle arrest in G1 phase within ovarian cancer cells. More importantly, NDRG2 overexpression significantly enhanced the suppressive roles of cisplatin (DDP) in ovarian cancer cell viability. On the contrary, NDRG2 silence exerted opposing effects on ovarian cancer cells. Conclusions In summary, we provide a solid experimental basis demonstrating the tumor-suppressive effects of NDRG2 in inhibiting the cell proliferation, enhancing the cell apoptosis, eliciting the cell cycle arrest in G1 phase, and promoting the suppressive effects of DDP on the viability of ovarian cancer cells. NDRG2 administration presents a potent adjuvant treatment for ovarian cancer therapy.
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Shi J, Zheng H, Yuan L. High NDRG3 expression facilitates HCC metastasis by promoting nuclear translocation of β-catenin. BMB Rep 2020. [PMID: 31072445 PMCID: PMC6675243 DOI: 10.5483/bmbrep.2019.52.7.201] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
NDRG1 has been reported to exert pivotal roles in tumor progression and metastasis via Wnt/β-catenin signaling pathway. However, little is known about the role of NDRG3 in hepatocarcinogenesis despite its classification in the same subfamily of NDRG1. The present study was aimed to characterize the expression pattern and understand the biological roles of NDRG3 in hepatocarcinogenesis, as a means to exploit its therapeutic potential. It was observed that NDRG3 was up-regulated in HCC tissues and higher NDRG3 expression was associated with significantly shorter overall survival. Furthermore, a lower level of NDRG3 exhibited marked positive correlation with metastasis-free survival. In vitro and in vivo experiments revealed that knock-down of NDRG3 inhibits HCC metastasis and angiogenesis. We further demonstrated that activation of WNT/β-catenin signaling and enhanced CSC-like properties were responsible for NDRG3- mediated promoting effect on HCC. In conclusion, the principal findings demonstrated that high NDRG3 expression facilitates HCC metastasis via regulating the turnover of β-catenin, as well as provides a potential therapeutic target for future therapeutic interventions.
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Affiliation(s)
- JiKui Shi
- Department of Critical Care Medicine, Jining NO.1 People's Hospital, Jining 272011, P.R. China
| | - HongZhen Zheng
- Department of Oncology, Changzheng Hospital, Second Military Medical University, Shanghai 200040, P.R. China
| | - LingYan Yuan
- Department of Oncology, Changzheng Hospital, Second Military Medical University, Shanghai 200040, P.R. China
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29
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Structural and Biophysical Analyses of Human N-Myc Downstream-Regulated Gene 3 (NDRG3) Protein. Biomolecules 2020; 10:biom10010090. [PMID: 31935861 PMCID: PMC7022630 DOI: 10.3390/biom10010090] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 12/31/2019] [Accepted: 01/01/2020] [Indexed: 01/07/2023] Open
Abstract
The N-Myc downstream-regulated gene (NDRG) family belongs to the α/β-hydrolase fold and is known to exert various physiologic functions in cell proliferation, differentiation, and hypoxia-induced cancer metabolism. In particular, NDRG3 is closely related to proliferation and migration of prostate cancer cells, and recent studies reported its implication in lactate-triggered hypoxia responses or tumorigenesis. However, the underlying mechanism for the functions of NDRG3 remains unclear. Here, we report the crystal structure of human NDRG3 at 2.2 Å resolution, with six molecules in an asymmetric unit. While NDRG3 adopts the α/β-hydrolase fold, complete substitution of the canonical catalytic triad residues to non-reactive residues and steric hindrance around the pseudo-active site seem to disable the α/β-hydrolase activity. While NDRG3 shares a high similarity to NDRG2 in terms of amino acid sequence and structure, NDRG3 exhibited remarkable structural differences in a flexible loop corresponding to helix α6 of NDRG2 that is responsible for tumor suppression. Thus, this flexible loop region seems to play a distinct role in oncogenic progression induced by NDRG3. Collectively, our studies could provide structural and biophysical insights into the molecular characteristics of NDRG3.
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30
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NDRG2 Expression Correlates with Neurofibrillary Tangles and Microglial Pathology in the Ageing Brain. Int J Mol Sci 2020; 21:ijms21010340. [PMID: 31947996 PMCID: PMC6982267 DOI: 10.3390/ijms21010340] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 01/02/2020] [Indexed: 11/17/2022] Open
Abstract
Astrocytes play a major role in the pathogenesis of a range of neurodegenerative diseases, including Alzheimer’s disease (AD), undergoing dramatic morphological and molecular changes that can cause potentially both beneficial and detrimental effects. They comprise a heterogeneous population, requiring a panel of specific phenotype markers to identify astrocyte subtypes, changes in function and their relation to pathology. This study aimed to characterise expression of the astrocyte marker N-myc downstream regulated gene 2 (NDRG2) in the ageing brain, investigate the relationship between NDRG2 and a panel of astrocyte markers, and relate NDRG2 expression to pathology. NDRG2 specifically immunolabelled the cell body and radiating processes of astrocytes in the temporal cortex of the Cognitive Function and Ageing Study (CFAS) neuropathology cohort. Expression of NDRG2 did not correlate with other astrocyte markers, including glial fibrillary acidic protein (GFAP), excitatory amino acid transporter 2 (EAAT2) and glutamine synthetase (GS). NDRG2 showed a relationship to AT8+ neurofibrillary tangles (p = 0.001) and CD68+ microglia (p = 0.047), but not β-amyloid plaques or astrocyte nuclear γH2AX immunoreactivity, a marker of DNA damage response. These findings provide new insight into the astrocyte response to pathology in the ageing brain, and suggest NDRG2 may be a potential target to modulate this response.
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Wijasa TS, Sylvester M, Brocke-Ahmadinejad N, Schwartz S, Santarelli F, Gieselmann V, Klockgether T, Brosseron F, Heneka MT. Quantitative proteomics of synaptosome S-nitrosylation in Alzheimer's disease. J Neurochem 2019; 152:710-726. [PMID: 31520481 DOI: 10.1111/jnc.14870] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 08/23/2019] [Accepted: 09/04/2019] [Indexed: 12/20/2022]
Abstract
Increasing evidence suggests that both synaptic loss and neuroinflammation constitute early pathologic hallmarks of Alzheimer's disease. A downstream event during inflammatory activation of microglia and astrocytes is the induction of nitric oxide synthase type 2, resulting in an increased release of nitric oxide and the post-translational S-nitrosylation of protein cysteine residues. Both early events, inflammation and synaptic dysfunction, could be connected if this excess nitrosylation occurs on synaptic proteins. In the long term, such changes could provide new insight into patho-mechanisms as well as biomarker candidates from the early stages of disease progression. This study investigated S-nitrosylation in synaptosomal proteins isolated from APP/PS1 model mice in comparison to wild type and NOS2-/- mice, as well as human control, mild cognitive impairment and Alzheimer's disease brain tissues. Proteomics data were obtained using an established protocol utilizing an isobaric mass tag method, followed by nanocapillary high performance liquid chromatography tandem mass spectrometry. Statistical analysis identified the S-nitrosylation sites most likely derived from an increase in nitric oxide (NO) in dependence of presence of AD pathology, age and the key enzyme NOS2. The resulting list of candidate proteins is discussed considering function, previous findings in the context of neurodegeneration, and the potential for further validation studies.
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Affiliation(s)
| | - Marc Sylvester
- Institute of Biochemistry and Molecular Biology, University of Bonn, Bonn, Germany
| | | | - Stephanie Schwartz
- Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany
| | | | - Volkmar Gieselmann
- Institute of Biochemistry and Molecular Biology, University of Bonn, Bonn, Germany
| | - Thomas Klockgether
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.,Department of Neurology, University of Bonn, Bonn, Germany
| | | | - Michael T Heneka
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.,Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany
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32
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Ge F, Zhang P, Niu J, Pei X, Lian C, Yu R, Ma R, Zhang Y, Zhu Z, Sun K. NDRG2 and TLR7 as novel DNA methylation prognostic signatures for acute myelocytic leukemia. J Cell Physiol 2019; 235:3790-3797. [PMID: 31613009 DOI: 10.1002/jcp.29273] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 09/27/2019] [Indexed: 12/20/2022]
Abstract
Acute myelocytic leukemia (AML) is an aggressive malignant tumor and typically fatal without treatment. Identification and development of novel biomarkers could be beneficial for the diagnosis and prognosis of AML patients. Here, we aimed to identify the accurate DNA methylation prognostic signatures for AML patients. The DNA methylation data of AML patients and corresponding clinical information were retrieved from The Cancer Genome Atlas database. CPG sites that correlates closely with the survival of the AML patients were identified and further combined into CPG sites pairs to screen the survival-related pairs. The prognostic signatures were identified by the C-index and forward search algorithms and validated by the verification group. Finally, the functional enrichment analysis was performed on these CPG sites. As a result, a total of 498 CPG sites associated with the overall survival of AML patients was obtained. A prognostic signature composed of 10 CPG sites pairs was obtained and validated. The functional enrichment analysis showed prognostic genes were mainly enriched in tumor protein processing, cell differentiation, blood leukocyte immunity, and platelet growth factor pathways. In summary, we identified two accurate prognostic methylation signatures (NDRG2 and TLR7), which would be served as a novel therapy target for AML.
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Affiliation(s)
- Fei Ge
- Department of Haematology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan, China
| | - Ping Zhang
- Department of Haematology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan, China
| | - Junwei Niu
- Department of Haematology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan, China
| | - Xiaohang Pei
- Department of Haematology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan, China
| | - Cheng Lian
- Department of Haematology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan, China
| | - Runhong Yu
- Department of Haematology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan, China
| | - Rongjun Ma
- Department of Haematology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan, China
| | - Yin Zhang
- Department of Haematology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan, China
| | - Zunmin Zhu
- Department of Haematology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan, China
| | - Kai Sun
- Department of Haematology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan, China
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33
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Han L, Zan Y, Huang C, Zhang S. NELFE promoted pancreatic cancer metastasis and the epithelial‑to‑mesenchymal transition by decreasing the stabilization of NDRG2 mRNA. Int J Oncol 2019; 55:1313-1323. [PMID: 31638184 PMCID: PMC6831195 DOI: 10.3892/ijo.2019.4890] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Accepted: 09/20/2019] [Indexed: 12/17/2022] Open
Abstract
Negative elongation factor E (NELFE) has been demonstrated to promote cancer progression as an RNA‑binding protein (RBP). However, the expression patterns, biological role and molecular mechanism of NELFE in pancreatic cancer (PC) remain largely unknown. The expression levels of NELFE in 120 pairs of PC tissues and adjacent non‑tumor clinical samples collected from patients with PC were examined via reverse transcription‑quantitative (RT‑q) PCR and immunohistochemistry. The mRNA expression levels of NELFE, N‑Myc downstream‑regulated gene 2 (NDRG2), c‑Myc, survivin and cyclin D1 were detected via RT‑qPCR. The protein expression levels of NELFE, NDRG2, total β‑catenin, nuclear β‑catenin, cytosolic β‑catenin, E‑cadherin, N‑cadherin and Vimentin were measured by western blotting. NELFE and NDRG2 were then knocked‑down by short hairpin (sh)RNA. PC cell proliferation was detected by MTT and colony formation assays. Invasion and migration were detected by transwell assays. The interaction between NELFE and NDRG2 was detected by luciferase reporter assays, mRNA decay assays and RNA immunoprecipitation. NELFE expression was increased in PC tissues compared with the paired non‑cancerous tissues. NELFE expression was upregulated in PC cells when compared with normal pancreatic cells (HPDE6‑C7). The present study revealed that knockdown of NELFE inhibited the proliferation, invasion and migration of PC cells. In addition, transfection of the sh‑NELFE vector inhibited the epithelial‑to‑mesenchymal transition in PC cells by suppressing the expression and nuclear accumulation of β‑catenin. Further mechanistic studies revealed that NELFE activates the Wnt/β‑catenin signaling pathway by decreasing the stabilization of NDRG2 mRNA in PC. To the best of our knowledge, these results revealed the promotional function of NELFE on PC tumorigenesis and metastasis for the first time, helping to provide a promising strategy for the treatment of patients with PC.
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Affiliation(s)
- Lili Han
- Department of Oncology, The Second Affiliated Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Ying Zan
- Department of Oncology, The Second Affiliated Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Chen Huang
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Shuqun Zhang
- Department of Oncology, The Second Affiliated Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
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34
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Schonkeren SL, Massen M, van der Horst R, Koch A, Vaes N, Melotte V. Nervous NDRGs: the N-myc downstream-regulated gene family in the central and peripheral nervous system. Neurogenetics 2019; 20:173-186. [PMID: 31485792 PMCID: PMC6754360 DOI: 10.1007/s10048-019-00587-0] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 08/22/2019] [Indexed: 02/07/2023]
Abstract
The N-Myc downstream-regulated gene (NDRG) family consists of four members (NDRG1, NDRG2, NDRG3, NDRG4) that are differentially expressed in various organs and function in important processes, like cell proliferation and differentiation. In the last couple of decades, interest in this family has risen due to its connection with several disorders of the nervous system including Charcot-Marie-Tooth disease and dementia, as well as nervous system cancers. By combining a literature review with in silico data analysis of publicly available datasets, such as the Mouse Brain Atlas, BrainSpan, the Genotype-Tissue Expression (GTEx) project, and Gene Expression Omnibus (GEO) datasets, this review summarizes the expression and functions of the NDRG family in the healthy and diseased nervous system. We here show that the NDRGs have a differential, relatively cell type-specific, expression pattern in the nervous system. Even though NDRGs share functionalities, like a role in vesicle trafficking, stress response, and neurite outgrowth, other functionalities seem to be unique to a specific member, e.g., the role of NDRG1 in myelination. Furthermore, mutations, phosphorylation, or changes in expression of NDRGs are related to nervous system diseases, including peripheral neuropathy and different forms of dementia. Moreover, NDRG1, NDRG2, and NDRG4 are all involved in cancers of the nervous system, such as glioma, neuroblastoma, or meningioma. All in all, our review elucidates that although the NDRGs belong to the same gene family and share some functional features, they should be considered unique in their expression patterns and functional importance for nervous system development and neuronal diseases.
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Affiliation(s)
- Simone L Schonkeren
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 616, 6200 MD, Maastricht, The Netherlands
| | - Maartje Massen
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 616, 6200 MD, Maastricht, The Netherlands
| | - Raisa van der Horst
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 616, 6200 MD, Maastricht, The Netherlands
| | - Alexander Koch
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 616, 6200 MD, Maastricht, The Netherlands
| | - Nathalie Vaes
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 616, 6200 MD, Maastricht, The Netherlands
| | - Veerle Melotte
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
- Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
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35
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The tumor suppressor NDRG2 cooperates with an mTORC1 inhibitor to suppress the Warburg effect in renal cell carcinoma. Invest New Drugs 2019; 38:956-966. [DOI: 10.1007/s10637-019-00839-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 07/12/2019] [Indexed: 10/26/2022]
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36
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Guo Y, Li X, Sun X, Wang J, Yang X, Zhou X, Liu X, Liu W, Yuan J, Yao L, Li X, Shen L. Combined Aberrant Expression of NDRG2 and LDHA Predicts Hepatocellular Carcinoma Prognosis and Mediates the Anti-tumor Effect of Gemcitabine. Int J Biol Sci 2019; 15:1771-1786. [PMID: 31523182 PMCID: PMC6743297 DOI: 10.7150/ijbs.35094] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 06/17/2019] [Indexed: 01/13/2023] Open
Abstract
The Warburg effect is one of the important hallmarks of cancer. The activation of oncogene and inactivation of tumor suppressor gene contribute to the enhancement of glycolytic enzymes and the Warburg effect. The N-myc downstream regulated gene 2 (NDRG2) is a tumor suppressor gene and is frequently lost in various types of cancer. However, little is known about glycolytic function and therapeutic value of NDRG2 in hepatocellular carcinoma (HCC). In this study, we found that NDRG2 and lactate dehydrogenase A (LDHA) were aberrantly expressed in HCC and were closely related to the Warburg effect. The correlation between NDRG2 and LDHA expression predicted HCC prognosis and the clinical response to chemotherapy. NDRG2 expression was significantly decreased while LDHA expression was increased in HCC specimens. NDRG2 and LDHA expression was significantly correlated with differentiation status, vascular invasion, and TNM stage of HCC. NDRG2 inhibited LDHA expression, the Warburg effect and the growth of HCC cells. Furthermore, NDRG2 mediated gemcitabine-induced inhibition of LDHA expression and the Warburg effect in HCC cells. Taken together, our data suggest that NDRG2 plays an important role in inhibiting the Warburg effect and the malignant growth of HCC via LDHA. NDRG2 combined with LDHA might be powerful prognostic biomarkers and targets for chemotherapy treatment of HCC.
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Affiliation(s)
- Yan Guo
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Xi'an Li
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Xiang Sun
- Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Jiancai Wang
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Xu Yang
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Xin Zhou
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Xinping Liu
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Wenchao Liu
- Department of Oncology, State Key Discipline of Cell Biology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Jianlin Yuan
- Department of Urology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Libo Yao
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Xia Li
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Lan Shen
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
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37
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Yin A, Guo H, Tao L, Cai G, Wang Y, Yao L, Xiong L, Zhang J, Li Y. NDRG2 Protects the Brain from Excitotoxicity by Facilitating Interstitial Glutamate Uptake. Transl Stroke Res 2019; 11:214-227. [PMID: 31250377 PMCID: PMC7067740 DOI: 10.1007/s12975-019-00708-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Revised: 04/22/2019] [Accepted: 05/27/2019] [Indexed: 02/07/2023]
Abstract
Glutamate is a prominent neurotransmitter responsible for excitatory synaptic transmission and is taken up by sodium-dependent excitatory amino acid transporters (EAATs) on astrocytes to maintain synaptic homeostasis. Here, we report that N-myc downstream regulated gene 2 (NDRG2), a known tumor suppressor, is required to facilitate astroglial glutamate uptake and protect the brain from glutamate excitotoxicity after ischemia. NDRG2 knockout (Ndrg2-/-) mice exhibited an increase in cerebral interstitial glutamate and a reduction in glutamate uptake into astrocytes. The ability of NDRG2 to control EAAT-mediated glutamate uptake into astrocytes required NDRG2 to interact with and promote the function of Na+/K+-ATPase β1, which could be disrupted by a Na+/K+-ATPase β1 peptide. The deletion of NDRG2 or treatment with the Na+/K+-ATPase β1 peptide significantly increased neuronal death upon a glutamate challenge and aggravated brain damage after ischemia. Our findings demonstrate that NDRG2 plays a pivotal role in promoting astroglial glutamate uptake from the interstitial space and protecting the brain from glutamate excitotoxicity.
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Affiliation(s)
- Anqi Yin
- Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Hang Guo
- Department of Anesthesiology, PLA Army General Hospital, Beijing, 100700, China
| | - Liang Tao
- Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Guohong Cai
- Institute of Neuroscience, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Yazhou Wang
- Institute of Neuroscience, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Libo Yao
- Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, 169 Changle West Road, Xi'an, 710032, Shaanxi, China
| | - Lize Xiong
- Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Jian Zhang
- Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, 169 Changle West Road, Xi'an, 710032, Shaanxi, China.
| | - Yan Li
- Department of Anesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.
- Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, Shaanxi, China.
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38
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Neuroprotective Influence of miR-301a Inhibition in Experimental Cerebral Ischemia/Reperfusion Rat Models Through Targeting NDRG2. J Mol Neurosci 2019; 68:144-152. [PMID: 30895440 DOI: 10.1007/s12031-019-01293-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 03/07/2019] [Indexed: 12/27/2022]
Abstract
The objective of this study is to find out the potential influence of miR-301a in an experimental cerebral ischemia-reperfusion (I/R) rat model through targeting NDRG2. Rats with cerebral I/R injury were constructed and classified into model, miR-301a inhibitor, miR-301a mimic, NC (negative control), siNDRG2, NDRG2, and miR-301a inhibitor + si-NDRG2 groups, as well as another sham group. Cerebral infarct volume and cell apoptosis were observed by TTC staining and TUNEL staining. The targeting relationship between miR-301a and NDRG2 was verified by luciferase assay. ELISA, qRT-PCR, and Western blot were used to detect the expressions of related molecules. Compared with sham group, rats in the model group had elevated neurological function score and infarct volume; meanwhile, the cell apoptosis rate and inflammatory response were also increased with enhanced expression of miR-301a and NDRG2 (all P < 0.05). These changes were worsened in the miR-301a mimic and si-NDRG2 groups. Conversely, those rats in the miR-301a inhibitor and NDRG2 groups presented increased NDRG2, and at the same time, other above concerning factors also exhibited opposite tendencies (all P < 0.05). Dual-luciferase reporter gene assay confirmed that NDRG2 was a target gene of miR-301a, and si-NDRG2 could reverse the neuroprotective effect of miR-301a inhibitor in rats with cerebral I/R injury. Inhibiting miR-301a has a neuroprotective effect on rats with cerebral I/R injury to ameliorate cell apoptosis and inflammatory response through possibly targeting NDRG2.
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39
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Truong VT, Tran DDT, Dang CT. Collision Occurrence of Meningioma and Astrocytoma: A Case Report and Literature Review. Asian J Neurosurg 2019; 14:938-942. [PMID: 31497134 PMCID: PMC6703018 DOI: 10.4103/ajns.ajns_97_19] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
A case of collision tumors occurring between two distinct primary brain tumors is reported. A 61-year-old female without history of radiotherapy or phakomatosis presented with progressive ly increasing headache and left hemiparesis. Investigation revealed a meningioma and a Grade II astrocytoma in the right frontal lobe. Simultaneous development of a meningioma and a low-grade glioma at adjacent sites is extremely rare. This is the third case reported in the literature. Some hypotheses are proposed to explain this phenomenon but most likely represent a coincidental event.
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Affiliation(s)
- Van Tri Truong
- Department of Neurosurgery, Hue University Hospital, Hue University of Medicine and Pharmacy, Hue University, Hue City, Vietnam.,Division of Orthopedics, Central Hospital of University of Montreal, University of Montreal, Montreal, Canada
| | - Duc Duy Tri Tran
- Department of Neurosurgery, Hue University Hospital, Hue University of Medicine and Pharmacy, Hue University, Hue City, Vietnam.,Department of Neurosurgery, Xuyen A Hospital, Ho Chi Minh City, Vietnam
| | - Cong Thuan Dang
- Department of Pathology, Hue University Hospital, Hue University of Medicine and Pharmacy, Hue University, Hue City, Vietnam
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40
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Jin PP, Xia F, Ma BF, Li Z, Zhang GF, Deng YC, Tu ZL, Zhang XX, Hou SX. Spatiotemporal expression of NDRG2 in the human fetal brain. Ann Anat 2018; 221:148-155. [PMID: 30312765 DOI: 10.1016/j.aanat.2018.09.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 08/06/2018] [Accepted: 09/26/2018] [Indexed: 01/08/2023]
Abstract
N-myc downstream-regulated gene 2 (NDRG2) has been implicated in the development of central nervous system and brain diseases such as brain tumors, ischemic stroke and neurodegenerative disorders. However, it remains unclear that the spatiotemporal distribution of NDRG2 in the human fetal brain. In this study, we examined the expression pattern of NDRG2 in different regions of human fetal brain at 16-28 gestational weeks (GWs) by using RT-PCR, western blot and immunohistochemistry. Firstly, RT-PCR revealed that mRNA of NDRG2 was detected in the human brain regions of fetuses at 16-28 GWs such as medulla oblongata (MdO), mesencephalon (MeE), cerebellum (Cbl), frontal lobe (Fr), ventricular (VZ)/subventricular zone (SVZ) and hippocampus (hip), and the expressions of NDRG2 mRNA in these human fetal brain regions were increased with gestational maturation. Furthermore, western blot and immunohistochemistry results revealed that at 28 GWs, the expression of NDRG2 protein was restricted to the MdO's olivary nucleus, MeE's aqueduct, cerebellar internal granular layers, cerebral cortex of the Fr, VZ/SVZ of lateral ventricle, and hippocampal dentate gyrus, and highest expression in the VZ/SVZ, and lowest in the MeE. Finally, double immunohistochemistry results showed that NDRG2 in the MdO, Cbl and VZ/SV at 28 GWS was mainly expressed in neurons (NeuN positive cells), and in some astrocytes (GFAP positive cells). Taken together, these results suggest that NDRG2 is mainly expressed in human fetal neurons of various brain regions during development, which may be involved in neuronal growth and maturation.
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Affiliation(s)
- Peng-Peng Jin
- Center of Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China
| | - Feng Xia
- Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Bin-Fang Ma
- Department of Histology and Embryology, Fourth Military Medical University, Xi'an 710032, China
| | - Zhen Li
- Department of Histology and Embryology, Fourth Military Medical University, Xi'an 710032, China
| | - Guo-Feng Zhang
- Department of Neurology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China
| | - Yan-Chun Deng
- Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Zhi-Lan Tu
- Department of Neurology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China
| | - Xing-Xing Zhang
- Departments of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Shuang-Xing Hou
- Department of Neurology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China.
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41
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Abbastabar M, Kheyrollah M, Azizian K, Bagherlou N, Tehrani SS, Maniati M, Karimian A. Multiple functions of p27 in cell cycle, apoptosis, epigenetic modification and transcriptional regulation for the control of cell growth: A double-edged sword protein. DNA Repair (Amst) 2018; 69:63-72. [PMID: 30075372 DOI: 10.1016/j.dnarep.2018.07.008] [Citation(s) in RCA: 139] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2018] [Revised: 07/19/2018] [Accepted: 07/19/2018] [Indexed: 01/27/2023]
Abstract
The cell cycle is controlled by precise mechanisms to prevent malignancies such as cancer, and the cell needs these tight and advanced controls. Cyclin dependent kinase inhibitor p27 (also known as KIP1) is a factor that inhibits the progression of the cell cycle by using specific molecular mechanisms. The inhibitory effect of p27 on the cell cycle is mediated by CDKs inhibition. Other important functions of p27 include cell proliferation, cell differentiation and apoptosis. Post- translational modification of p27 by phosphorylation and ubiquitination respectively regulates interaction between p27 and cyclin/CDK complex and degradation of p27. In this review, we focus on the multiple function of p27 in cell cycle regulation, apoptosis, epigenetic modifications and post- translational modification, and briefly discuss the mechanisms and factors that have important roles in p27 functions.
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Affiliation(s)
- Maryam Abbastabar
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Kheyrollah
- Department of Molecular Medicine, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Khalil Azizian
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Science, Tabriz, Iran
| | - Nazanin Bagherlou
- Department of Biology, Faculty of Science, University of Mohaghegh Ardabili, Ardabil, Iran
| | - Sadra Samavarchi Tehrani
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran; Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Mahmood Maniati
- Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ansar Karimian
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran; Cancer & Immunology Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran; Student Research Committee, Babol University of Medical Sciences, Babol, Iran.
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42
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Li T, Sun R, Lu M, Chang J, Meng X, Wu H. NDRG3 facilitates colorectal cancer metastasis through activating Src phosphorylation. Onco Targets Ther 2018; 11:2843-2852. [PMID: 29844682 PMCID: PMC5961472 DOI: 10.2147/ott.s156814] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Background NDRG3 is an N-myc downregulated gene (NDRG). The aim of this article was to identify the role of NDRG3 in colorectal cancer (CRC) and to determine the mechanism underlying its function. Methods Using immunohistochemical staining, expression and clinicopathological variables of NDRG3 were analyzed in 170 CRC samples. Overexpression of NDRG3 was employed in SW1116 cells, downregulation of NDRG3 was achieved in RKO cells, then migration and invasion assays were performed in vitro, and a mouse model was constructed in vivo. Results Increased expression of NDRG3 was observed in primary CRC tissues, and this expression was correlated with distant metastasis. Consistently, ectopic expression of NDRG3 in SW1116 cells enhanced cell migration and invasion, while knockdown of NDRG3 in RKO cells significantly suppressed CRC cell metastasis. The portal vein injection models suggested that NDRG3 overexpression facilitates liver metastasis. These events were associated with the phosphorylation of Src (c-Src) at Tyr 419 site. Conclusion Our results showed that NDRG3 facilitates CRC migration and invasion by activating Src phosphorylation, suggesting the role of NDRG3 as a candidate oncogene.
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Affiliation(s)
- Ting Li
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, He Fei, 230222, China
| | - Ruochuan Sun
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, He Fei, 230222, China
| | - Mingdian Lu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, He Fei, 230222, China
| | - Jiacong Chang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, He Fei, 230222, China
| | - Xiangling Meng
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, He Fei, 230222, China
| | - Huo Wu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, He Fei, 230222, China
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43
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Wei Y, Yu S, Zhang Y, Zhang Y, Zhao H, Xiao Z, Yao L, Chen S, Zhang J. NDRG2 promotes adriamycin sensitivity through a Bad/p53 complex at the mitochondria in breast cancer. Oncotarget 2018; 8:29038-29047. [PMID: 28423695 PMCID: PMC5438710 DOI: 10.18632/oncotarget.16035] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 02/20/2017] [Indexed: 11/25/2022] Open
Abstract
Chemo-resistance presents a difficult challenge for the treatment of breast cancer. Our previous study showed that N-Myc downstream-regulated gene 2 (NDRG2) is involved in p53-mediated apoptosis induced by chemotherapy, through a mechanism that has so far remained obscure. Here, we explored the role of NDRG2 in chemo-resistance with a focus on Adriamycin (ADR) and found that NDRG2 expression decreased in ADR resistance breast cancer cells. Interestingly, NDRG2 can promote ADR sensitivity by inhibiting proliferation, enhancing cellular damage responses, and promoting apoptosis in a p53-dependent manner. We also found that NDRG2 could upregulate Bad expression by increasing its half-life, which is associated with p53 to mitochondria. Hence, our collective data provided the first evidence that NDRG2 promoting sensitivity of breast cancer is dependent on p53 by preventing p53 from entering the nucleus rather than changing its expression.
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Affiliation(s)
- Yifang Wei
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Shentong Yu
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.,Department of Pathology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Yongping Zhang
- Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, 310058, Hangzhou, China
| | - Yuan Zhang
- Department of Oncology, The State Key Discipline of Cell Biology, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Huadong Zhao
- Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, 710038, Xi'an, China
| | - Zhixiong Xiao
- College of Life Science, Sichuan University, Chendu, 610065, Sichuan, China
| | - Libo Yao
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Suning Chen
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.,Department of Pharmacy, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Jian Zhang
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
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44
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von Karstedt S. NDRG2 programs tumor-associated macrophages for tumor support. Cell Death Dis 2018; 9:294. [PMID: 29463798 PMCID: PMC5833842 DOI: 10.1038/s41419-018-0268-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Accepted: 01/04/2018] [Indexed: 11/09/2022]
Affiliation(s)
- Silvia von Karstedt
- Department of Translational Genomics, University Hospital of Cologne, Cologne, Germany. .,Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
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45
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Li M, Lai X, Zhao Y, Zhang Y, Li M, Li D, Kong J, Zhang Y, Jing P, Li H, Qin H, Shen L, Yao L, Li J, Dou K, Zhang J. Loss of NDRG2 in liver microenvironment inhibits cancer liver metastasis by regulating tumor associate macrophages polarization. Cell Death Dis 2018; 9:248. [PMID: 29445150 PMCID: PMC5833557 DOI: 10.1038/s41419-018-0284-8] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 12/25/2017] [Accepted: 12/27/2017] [Indexed: 02/07/2023]
Abstract
The liver is the predominant metastatic site for several types of malignancies. Tumor-associated macrophages (TAMs) in the liver play crucial roles in the metastasis process. Shifting tumor-promoting M2-like TAMs toward the M1-like phenotype, which exerts tumor suppressor functions via phagocytosis and the secretion of inhibitory factors, may be a potential therapeutic strategy for liver cancer metastasis treatment. We first cloned NDRG2 (N-myc downstream-regulated gene 2) and verified its tumor suppressor role in multiple solid tumors, including colorectal cancer and hepatocellular carcinoma. However, its role in the tumor-associated liver microenvironment, especially in TAMs, has not been illustrated. By establishing a liver cancer metastasis model in wild-type (WT) and Ndrg2 knockout (Ndrg2−/−) mice, we found that the loss of the tumor suppressor Ndrg2 in liver microenvironment significantly suppressed the growth of liver colonies. In addition, this process was accompanied by a higher proportion of M1-like TAM infiltration in Ndrg2−/− mice. Interestingly, bone marrow (BM) transplantation revealed that BM-derived macrophages (BMDMs) rather than liver resident Kupffer cells were responsible for the inhibitory effect. We further demonstrated that loss of Ndrg2 influenced TAM polarization via the NF-κB pathway. Inhibition of IκBα phosphorylation in cancer cell-conditioned medium-stimulated BMDMs decreased M1 marker expression in Ndrg2−/− macrophages. Finally, in vitro, invasion, migration, and proliferation assays confirmed that NF-κB participated in the tumor suppressor function of Ndrg2−/− macrophages. Collectively, our findings highlight the role of NDRG2 in the regulation of TAM polarization and its function in promoting cancer liver metastasis.
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Affiliation(s)
- Mengyang Li
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.,Department of Hepatobiliary and Pancreas Surgery, Xijing Hospital Fourth Military Medical University, Xi'an, China
| | - Xiaofeng Lai
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China
| | - Ying Zhao
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.,State Key Laboratory of Cancer Biology, Institute of Digestive Diseases, Xijing Hospital The Fourth Military Medical University, Xi'an, China
| | - Yuan Zhang
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China
| | - Minghui Li
- Department of Orthopedics, Xijing Hospital Fourth Military Medical University, Xi'an, China
| | - Danxiu Li
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China
| | - Jing Kong
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital Fourth Military Medical University, Xi'an, China
| | - Yong Zhang
- Department of Pulmonary Medicine, Xijing Hospital Fourth Military Medical University, Xi'an, China
| | - Pengyu Jing
- Department of Thoracic Surgery, Tangdu Hospital Fourth Military Medical University, Xi'an, China
| | - Huichen Li
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China
| | - Hongyan Qin
- Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, China
| | - Liangliang Shen
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China
| | - Libo Yao
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China
| | - Jipeng Li
- State Key Laboratory of Cancer Biology, Institute of Digestive Diseases, Xijing Hospital The Fourth Military Medical University, Xi'an, China.
| | - Kefeng Dou
- Department of Hepatobiliary and Pancreas Surgery, Xijing Hospital Fourth Military Medical University, Xi'an, China.
| | - Jian Zhang
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.
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Park S, Oh SS, Lee KW, Lee YK, Kim NY, Kim JH, Yoo J, Kim KD. NDRG2 contributes to cisplatin sensitivity through modulation of BAK-to-Mcl-1 ratio. Cell Death Dis 2018; 9:30. [PMID: 29348517 PMCID: PMC5833685 DOI: 10.1038/s41419-017-0184-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Revised: 11/22/2017] [Accepted: 11/27/2017] [Indexed: 02/07/2023]
Abstract
The downregulation of N-Myc downstream-regulated gene 2 (NDRG2) is known to be associated with the progression and poor prognosis of several cancers. Sensitivity to anti-cancer may be associated with a good prognosis in cancer patients, and NDRG2, which is induced by p53, sensitizes the cells to chemotherapy. However, the unique function of NDRG2 as an inducer of apoptosis under chemotreatment has not been sufficiently studied. In this study, we investigated the role of NDRG2 in chemo-sensitivity, focusing on cisplatin in U937 histiocytic lymphoma, which has the loss-of-functional mutation in p53. NDRG2 promoted the sensitivity to cisplatin through the modulation of the BAK-to-Mcl-1 ratio. The degradation of Mcl-1 and increase in BAK were mediated by JNK activation and the eIF2α/p-eIF2α pathway, respectively, which depended on PKR activation in NDRG2-overexpressed U937 (U937-NDRG2) cells. NOX5 was highly expressed in U937-NDRG2 cells and contributed to ROS production after cisplatin treatment. ROS scavenging or NOX5-knockdown successfully inhibited the sensitivity of U937-NDRG2 cells to cisplatin. Taken together, these findings indicate that NDRG2 contributed to the increased sensitivity to ciplatin through the modulation of Bak-to-Mcl-1 ratio regulated by NOX5-ROS-PKR pathway; therefore, we suggest that NDRG2 may be a molecular target for improving the efficacy of drug treatment in cancer patients.
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Affiliation(s)
- Soojong Park
- Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju, 52828, Republic of Korea
| | - Sang-Seok Oh
- Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju, 52828, Republic of Korea
| | - Ki Won Lee
- Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju, 52828, Republic of Korea
| | - Yeon-Kyeong Lee
- Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju, 52828, Republic of Korea
| | - Nae Yu Kim
- Department of Internal Medicine, Eulji University School of Medicine, Daejeon, 35233, Republic of Korea
| | - Joo Heon Kim
- Department of Pathology, Eulji University School of Medicine, Daejeon, 35233, Republic of Korea
| | - Jiyun Yoo
- Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju, 52828, Republic of Korea.,Division of Life Science, Gyeongsang National University, Jinju, 52828, Republic of Korea
| | - Kwang Dong Kim
- Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju, 52828, Republic of Korea. .,Division of Life Science, Gyeongsang National University, Jinju, 52828, Republic of Korea. .,PMBBRC, Gyeongsang National University, Jinju, 52828, Republic of Korea.
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NDRG2 facilitates colorectal cancer differentiation through the regulation of Skp2-p21/p27 axis. Oncogene 2018; 37:1759-1774. [PMID: 29343851 PMCID: PMC5874257 DOI: 10.1038/s41388-017-0118-7] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Revised: 11/07/2017] [Accepted: 12/14/2017] [Indexed: 01/11/2023]
Abstract
Poorly differentiated colorectal cancers (CRCs) are more aggressive and lack targeted therapies. We and others previously reported the predominant role of tumor-suppressor NDRG2 in promoting CRC differentiation, but the underlying mechanism is largely unknown. Herein, we demonstrate that NDRG2 induction of CRC cell differentiation is dependent on the repression of E3 ligase Skp2 activity. In patients and Ndrg2 knockout mice, NDRG2 and Skp2 are negatively correlated and associated with cell differentiation stage. Further, NDRG2 suppression of Skp2 contributes to the inductions and stabilizations of p21 and p27, which are Skp2 target proteins for degradation. The reduction of either p21 or p27 levels by shRNA can decrease NDRG2-induced AKP activity and resume cell growth inhibition, thus both p21 and p27 are required for NDRG2 effect on the promotion of cell differentiation in CRCs. The mechanistic study shows that NDRG2 suppresses β-catenin nuclear translocation and decreases the occupancy of β-catenin/TCF complex on Skp2 promoter, potentially through dephosphorylating GSK-3β. By subjecting a series of NDRG2 deletion mutants to Skp2 expression, the loss of NH2-terminal domain can completely abolish NDRG2-dependent differentiation induction. Supporting the biological significance of the reciprocal relationship between NDRG2 and Skp2, an NDRG2low/Skp2high gene expression signature correlates with poor CRC patient outcome and could be considered as a diagnostic marker of CRCs.
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48
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Sheng X, Huang T, Qin J, Yang L, Sa ZQ, Li Q. Identification of the Differential Expression Profiles of Serum and Tissue Proteins During Rat Hepatocarcinogenesis. Technol Cancer Res Treat 2018; 17:1533034618756785. [PMID: 29478368 PMCID: PMC5833169 DOI: 10.1177/1533034618756785] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The pathogenesis of hepatocellular carcinoma is complex and not fully known yet. This study aims to screen and identify the differentially expressed proteins in peripheral blood and liver tissue samples from rat hepatocellular carcinoma and to further clarify the pathogenesis and discover the specific tumor markers and molecular targets of hepatocellular carcinoma. The hepatocellular carcinoma model of Wistar rats were induced by chemical carcinogen. The serum and liver tissue samples were obtained after induction for 2, 4, 8, 14, 18, and 21 weeks. The results showed that the clusterin (IPI00198667), heat shock protein a8 (IPI00208205), and N-myc downstream-regulated gene-2 (IPI00382069) being closely related to hepatocarcinogenesis were eventually identified from the 30 different proteins. As the time progressed, the serum levels of clusterin and heat shock protein a8 increased gradually during induced liver cancer in rats. However, the serum N-myc downstream-regulated gene 2 level in induced liver cancer in rats underwent biphasic changes, and the serum N-myc downstream-regulated gene 2 level decreased at the 8th week, increased at the 14th week, and then decreased significantly. Statistical difference occurred in protein expression of clusterin and heat shock protein a8 in liver tissues at the different time points. In the liver tissues, the N-myc downstream-regulated gene 2 level decreased gradually at the 8th week, increased gradually at the 14th week, and then decreased significantly after 14 weeks. The study demonstrated that heat shock protein a8, clusterin, and N-myc downstream-regulated gene 2 participated in the process of abnormal cell division, proliferation, and carcinogenesis of liver cells during hepatocarcinogenesis.
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MESH Headings
- Animals
- Biomarkers, Tumor/blood
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Hepatocellular/blood
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- Immunohistochemistry
- Liver/metabolism
- Liver/pathology
- Liver Neoplasms/blood
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Male
- Proteome
- Proteomics/methods
- Rats
- Transcriptome
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Affiliation(s)
- Xia Sheng
- 1 Department of pathology, Affiliated to the Third Hospital, Second Military Medical University, Shanghai, P.R. China
| | - Tao Huang
- 2 Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China
| | - Jianmin Qin
- 2 Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China
- 3 Department of general surgery, Affiliated to the Third Hospital, Second Military Medical University, Shanghai, P.R. China
| | - Lin Yang
- 2 Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China
| | - Zhong-Qiu Sa
- 2 Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China
| | - Qi Li
- 4 Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China
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Fu Q, Gao Y, Yang F, Mao T, Sun Z, Wang H, Song B, Li X. Suppression of microRNA-454 impedes the proliferation and invasion of prostate cancer cells by promoting N-myc downstream-regulated gene 2 and inhibiting WNT/β-catenin signaling. Biomed Pharmacother 2017; 97:120-127. [PMID: 29080452 DOI: 10.1016/j.biopha.2017.10.115] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Revised: 10/18/2017] [Accepted: 10/21/2017] [Indexed: 12/24/2022] Open
Abstract
MicroRNA-454 (miR-454) is emerging as critical regulator in tumorigenesis; it may function as an oncogene or a tumor suppressor. However, the role of miR-454 in prostate cancer remains unknown. In this study, we aimed to investigate the function and molecular mechanisms of miR-454 in prostate cancer. We found that miR-454 was highly expressed in prostate cancer tissues and cell lines (*p<0.05), as detected by real-time quantitative polymerase chain reaction (RT-qPCR). Cell counting kit-8 assay, colony formation assay and cell invasion assay showed that the inhibition of miR-454 significantly suppressed prostate cancer cell proliferation and invasion (*p<0.05), whereas the overexpression of miR-454 markedly promoted prostate cancer cell proliferation and invasion (*p<0.05). Bioinformatics analysis showed that N-myc downstream-regulated gene 2 (NDRG2), a well-known tumor suppressor, was identified as a potential target gene of miR-454. Dual-luciferase reporter assay showed that miR-454 directly targeted the 3'-untranslated region of NDRG2. RT-qPCR and western blot showed that miR-454 overexpression significantly decreased NDRG2 expression (*p<0.05), whereas miR-454 inhibition markedly promoted NDRG2 expression (*p<0.05). Spearman's correlation analysis showed that miR-454 expression was inversely correlated with NDRG2 expression in prostate cancer tissues (r=-0.8932; p<0.0001). Moreover, miR-454 inhibition significantly suppressed the protein expression of β-catenin (*p<0.05) and blocked the activation of WNT signaling (*p<0.05). In addition, small interfering RNA mediated NDRG2 knockdown significantly reversed the antitumor effect of miR-454 inhibition on prostate cancer cell proliferation and invasion (*p<0.05). Taken together, these results reveal an oncogenic role of miR-454, which promotes prostate cancer cell proliferation and invasion by downregulation of NDRG2. These results also suggest miR-454 as a potential therapeutic target for the treatment of prostate cancer.
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Affiliation(s)
- Qiang Fu
- Department of Urology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710038, China
| | - Yanyao Gao
- Department of Urology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710038, China
| | - Fan Yang
- Department of Urology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710038, China
| | - Tianci Mao
- Department of Urology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710038, China
| | - Zhenye Sun
- Department of Urology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710038, China
| | - He Wang
- Department of Urology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710038, China.
| | - Bin Song
- Department of Urology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710038, China.
| | - Xin Li
- Department of Urology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710038, China.
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50
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Li Y, Yin A, Sun X, Zhang M, Zhang J, Wang P, Xie R, Li W, Fan Z, Zhu Y, Wang H, Dong H, Wu S, Xiong L. Deficiency of tumor suppressor NDRG2 leads to attention deficit and hyperactive behavior. J Clin Invest 2017; 127:4270-4284. [PMID: 29058689 DOI: 10.1172/jci94455] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 09/12/2017] [Indexed: 12/14/2022] Open
Abstract
Attention-deficit/hyperactivity disorder (ADHD) is a prevalent psychiatric disorder in children. Although an imbalance of excitatory and inhibitory inputs has been proposed as contributing to this disorder, the mechanisms underlying this highly heterogeneous disease remain largely unknown. Here, we show that N-myc downstream-regulated gene 2 (NDRG2) deficiency is involved in the development of ADHD in both mice and humans. Ndrg2-knockout (Ndrg2-/-) mice exhibited ADHD-like symptoms characterized by attention deficits, hyperactivity, impulsivity, and impaired memory. Furthermore, interstitial glutamate levels and excitatory transmission were markedly increased in the brains of Ndrg2-/- mice due to reduced astroglial glutamate clearance. We developed an NDRG2 peptide that rescued astroglial glutamate clearance and reduced excitatory glutamate transmission in NDRG2-deficient astrocytes. Additionally, NDRG2 peptide treatment rescued ADHD-like hyperactivity in the Ndrg2-/- mice, while routine methylphenidate treatment had no effect on hyperactivity in these animals. Finally, children who were heterozygous for rs1998848, a SNP in NDRG2, had a higher risk of ADHD than children who were homozygous for rs1998848. Our results indicate that NDRG2 deficiency leads to ADHD phenotypes and that impaired astroglial glutamate clearance, a mechanism distinct from the well-established dopamine deficit hypothesis for ADHD, underlies the resultant behavioral abnormalities.
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Affiliation(s)
- Yan Li
- 1, Department of Anesthesiology and Perioperative Medicine.,2, Institute of Neuroscience.,3, Department of Biochemistry and Molecular Biology, and
| | - Anqi Yin
- 1, Department of Anesthesiology and Perioperative Medicine
| | - Xin Sun
- 4, Department of Pediatrics, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Ming Zhang
- 1, Department of Anesthesiology and Perioperative Medicine.,5, General Hospital of Chengdu Military Command, Chengdu, Sichuan, China
| | - Jianfang Zhang
- 6, Department of Gynecology and Obstetrics, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Ping Wang
- 4, Department of Pediatrics, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Rougang Xie
- 1, Department of Anesthesiology and Perioperative Medicine.,2, Institute of Neuroscience
| | - Wen Li
- 1, Department of Anesthesiology and Perioperative Medicine
| | - Ze Fan
- 1, Department of Anesthesiology and Perioperative Medicine
| | | | - Han Wang
- 7, School of Biology and Basic Medical Sciences, Medical College, Soochow University, Suzhou, Jiangsu, China
| | - Hailong Dong
- 1, Department of Anesthesiology and Perioperative Medicine
| | | | - Lize Xiong
- 1, Department of Anesthesiology and Perioperative Medicine
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